William Hamilton's worries about the future
of the human genome

A review by Gert Korthof   updated 12 Dec 2023 (first published 25 Aug 2011)

Bill Hamilton at the Kyoto Prize ceremony 1993 (list of winners). (images from the documentary captured with Open Movie Player and edited with GIMP Image Editor)

Philosopher Michael Ruse interviewed in the BBC documentary (2)

"Hamilton believed that some people were genetically inferior to others. We should take a stand against the slide into degeneration."
"... it would let the genetically inferior to survive and so would weaken society".

Volume 1 Evolution of Social Behaviour

Volume 2 Evolution of sex

Volume 3 Last Words

"If humans turn out to be near the Kondrashov limit —that is, if on average every gamete has one bad mutation created during the lifetime of its producer— it is obviously not going to be nearly enough to test a baby for the subset of the few hundreds or so of well-characterized genetic defects (...) There are certainly tens of thousands more possible mutations that the baby could have that have not been characterized well enough ..." (p. 465). (my emphasis)

"for me, tiny embryos that seem to be in fish-like stages of human development, or earlier, are genuinely fish-like or even more primitive. Indeed, I believe additionally that they experience less of pain, fear, and danger than fish experience. Because of this I would genuinely be happier 'terminating' such early human embryos in a Petri dish than I would be 'terminating' an adult fish in an aquarium." (p. 460).
"By kidding ourselves about some weird kindness to embryos, to neonates, and the like now, we are actually being very unkind to numerous far more sentient persons of the future." (p. 476)
"If one is going to kill a baby, clearly it is only tolerable for it to be killed painlessly" (p. 481 Vol 2 Narrow Roads).

William D. Hamilton (1936 - 2000) © James King-Holmes/Science Photo Library. printed in Vol 2 Narrow Roads

What others say

"One non-scientific and even political theme recurs throughout the autobiographical essays, and it is one that troubles many readers. Hamilton develops a eugenic argument, which was deeply felt and persistently argued. (...) It shocks many readers when Hamilton advocates infanticide; suggests the denial or in more emollient mode the strict regulation of fertility treatment; and worries about the long-term effects of saving the lives of mother and neonate with a Caesarean section." (...) It has to be said that the scientific basis of Hamilton's eugenic views is not established, though he provided interesting possible hypotheses."
"A start on an intellectual engagement with Hamilton's views has been made in the considered remarks of Haig (2003)"
(Narrow Roads Vol 3, chapter 20, p.447,448)

"I think that many of Hamilton's ideas on eugenics are naïve and misguided, but I support his plea that this should be a question on which one could have a reasoned, nonacrimonious exchange of views. The extent to which the human genome is deteriorating is an important question that should be squarely faced, rather than side-stepped."
David Haig (2003) (6)

"Don't you think that in the timescale in which medical treatment is going to lead to an increase in the frequency of deleterious genes, we are going to see techniques for actually changing the genes themselves (that is, eugenics)? If we can actually transform deleterious genes into beneficial genes in the germ line..." (Narrow Roads Vol 2 p.456).

"I do regard mutation accumulation as a problem." (38)

D I S C U S S I O N

Old and new eugenics

Dilemma: individual health versus the health of the human genome

The dilemma creates the paradox of civilization

"variations in gene sequence or expression of the human genome may have adaptive or maladaptive consequences, but they cannot be reduced to an error of nature that should be corrected. The hallmark of an enlightened society is its inclusion of homosexuality, ethnic differences and disabilities. Governments have spent time and money to accommodate people with visual and hearing impairments, helping them to navigate public places and find employment" (68).

Is the dilemma always real?

Unpreventable de novo mutations

Is the dilemma recognized by professionals?

What is the mutation frequency?

Who cares about future genomes?

The economic costs of mutational load

• The total economic impact of premature death and disability from cancer worldwide was $895 billion in 2008 (11).
• Congenital mental retardation afflicts about 51,000 children annually in the USA; the Centers for Disease Control and Prevention (CDC) estimate that each afflicted child will cost the US economy $1 million over the course of his or her life–that is, a collective cost of $51 billion (54).
• Preterm birth is a significant cost factor in healthcare.
• mental illness. In Europe in a typical year, about 165 million people — 38% (!) of the total population of 30 European countries — will have a fully developed mental illness (28). Brain disorders cost Europe almost €800 billion (US$1 trillion) a year – more than cancer, cardiovascular disease and diabetes put together (59). The proportion that can be attributed to genetic conditions is unspecified or unknown.
• spina bifida: The lifetime medical cost for a person with spina bifida was estimated to be $460,923 and nonmedical costs $56,511 in 2009 in the USA (56)
• Cystic Fibrosis. VX-770-Kalydeco (Ivacaftor), a drug that helps to reduce the symptoms of a subgroup of people with the hereditary disease CF (see above), costs $294,000 a year for the twice-daily pill, to be taken for a lifetime (82), (158). If all 1200 CF (G551D) patients would use VX-770-Kalydeco it would cost $352,800,000 per year or $3,5 billion per 10 year. But those patients are only 4% of the CF population in the US. The drug has side effects. The state of Arkansas last year [2015] settled a lawsuit filed by three people who said they had been denied access to the $300,000 Cystic Fibrosis drug Kalydeco (ivacaftor) because of the cost (193).
• Pompe disease: In the Netherlands the costs of treatment with Myozyme are €400,000 to 700,000 per patient per year and treatment is necessary lifelong (source). So it could easily mean some 30 million Euro for lifelong treatment (106).
• Fabry Disease: In the Netherlands enzyme replacement therapy costs about €200,00 per patient per year (106). Another 40 medicines which costs on average 2.5 million per year –for example Hunter syndrome– are possibly too expensive to be paid by the government (113).
• Maroteaux–Lamy syndrome: is a rare inherited disease. Naglazyme therapy costs $350,000 a year, and is one of the world's most expensive drugs (source).
• Diabetes: Diabetes is caused by low insulin levels and is partly caused by genetic factors (83). Total costs of diagnosed diabetes in the United States in 2007 is $174 billion; direct medical costs: $116 billion, and indirect costs (disability, work loss, premature mortality): $58 billion (source). Factoring in the additional costs of undiagnosed diabetes, prediabetes, and gestational diabetes brings the total cost of diabetes in the United States in 2007 to $218 billion. (209).
• autism. During the past decade, the US federal government has spent about US$1 billion researching the genetics of autism and only about $40 million on studies of possible environmental factors (67).
• breast cancer: because breast cancer is highly prevalent, it might have the highest price tag of any cancer by 2020. The costs of breastcancer treatment in 2010 is 16 billion US$ and is expected to rise to 20 billion by 2020 (91).
• β-thalassemia: Treating a baby costs up to $4900 a year, with fees increasing as the child grows. The disease strains health resources: in addition to monthly transfusions, patients may need regular iron chelation therapy through pills or a mechanical pump. The provincial and central governments have so far spent more than $80.7 million on genetic screening. (139).
• Sickle Cell Disease: The Cost of Living with Sickle Cell Disease: "New study reveals that people with sickle cell disease spend roughly $1.7 million on total lifetime medical costs" ... "raise questions about how medical advancements, like gene therapy, may one day factor into the cost of care." (207)
• China is contributing $470 million to the Human Variome Project, an international effort to catalog gene variations affecting human health.
• In 2010 the United States spent $5 billion on genetic tests (according to a United Health Group study published 12 March). That could go up to $25 billion within a decade. (Science, 16 Mar 2012).
• According to Statistics Netherlands the total costs spent on health and welfare in the Netherlands were 74.4 billion Euro in 2007. In 2010 an estimated 87.6 billion was spent (79).

1. Prevention:
   • Avoid mutagenic (genotoxic) substances in our environment: radioactivity, smoking, lead and other heavy metals in gasoline and paint, etc (132). Avoid having children in consanguineous marriage. Avoid certain foods that have a negative effect on the developing fetus during pregnancy. Women should start eating healthily well before they get pregnant (155). See also: euthenics.
   • Both father and mother should avoid having children at a later age (for mothers the age is 31 (71), some rare diseases have a tenfold increase in fathers older than 50 years (107). Reason: there is an increase in the frequency of chromosomal abnormalities in newborn children as a function of maternal and paternal age (72). Older males beget more mutations (128). Furthermore, at a higher age of the mother the risk for pregnancy complications is higher (Caesarean section and pre-eclampsia). Around 80% of de novo mutations seem to occur in the father's sperm and 20% in the mother's egg, says Joris Veltman.
   • Voluntary prevention of the birth of humans with known genetic diseases (genetic diseases run in families). The following is already happening or technically possible:
     • genetic counseling for parents (47)
     • Pre-marital genetic testing: for example, Ashkenazi communities already use genetic screening to make lists of suitable marital partners early in life to avoid their offspring developing painful Tay-Sachs disease and more than 20 similarly devastating diseases (148). Genetic Screening has reduced the birth rate of Tay-Sachs disease babies in the Ashkenazi Jewish community by at least 90% (167)
     • Pre-conceptional genetic carrier testing for couples (for example: Cystic fibrosis and Hemoglobinopathies)
     • Pre-Conception Testing: sequencing the DNA of sperm donors (120), (121), (122).
     • prenatal diagnosis of embryo during pregnancy. Potential to detect de novo mutations (173)
     • Preimplantation Genetic Diagnosis (PGD) in combination with IVF (131). Potential to detect de novo mutations (173)
     • Non-Invasive Prenatal genetic Testing (NIPT): detecting prenatal fetal DNA in maternal blood, making invasive procedures such as amniocentesis unnecessary (96) (97) (123), (124), (152)
     • fetal whole genome detection in maternal blood (103)
     • newborn screening: it is possible to screen newborns easily and cheaply for 50 rare disorders (149). However, there are more than 6,800 rare diseases. Altogether, rare diseases affect an estimated 25 million to 30 million Americans (182). So, this is a huge problem!
     • Rapid Whole-Genome Sequencing in newborns (116)
     Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis (93). More than 3528 monogenic diseases have been characterized (116). Currently, more than 1000 genetic tests are available from testing laboratories, or approximately 900 genetic tests according to Gene Tests Org (188). Example: because of genetic tests the number of children born with Tay Sachs in the United States have been reduced by 90% (57). Today it is economically feasible to test 448 severe recessive childhood diseases (58), and the number is increasing (64). A requirement for testing is that the mutations are known to cause disease. Hamilton claimed that prenatal diagnosis and germline gene therapy have little effect on the human genome. But since that time costs of sequencing a human genome has significantly decreased. In 2012 Oxford Nanopore Technologies (UK) said that it would soon be able to sequence a human genome in 15 minutes (105). A challenge is the fact that some (many) mutations are only deleterious in combination with other mutations (127) ('Genetic background problem'). Therefore, screening for 'standalone' deleterious mutants is not enough. Screening for combinations of 'neutral' mutations seems to be required. Which is a daunting task.
2. Therapy: (reorganised 26 March 2015)
   There are three main targets of genetic therapy: somatic, germline and mitochondrial.
   • Somatic gene therapy (see also box below): genome editing of human somatic cells aims to repair or eliminate a mutation that could cause disease (13),(14). It is directed at the body of the individual and does not repair the germline. Somatic gene therapies help the patient, not the descendants of the patient.
   • Germline gene therapy: corrects the germline (eggs, sperm, fertilised egg, embryo) and not somatic cells. A solution that benefits both the incipient patient and all its descendatns would be genetic therapy of the fertilised egg (before the first division). Only germline gene therapy is 'eugenic' (35). This is so far only an option if the mother has a mitochondrial disease (80). Repairing the genome by germline gene therapy is prohibited by law in many countries: around 40 countries discourage or ban it, in Europe 15 of 22 nations prohibit the modification of the germ line (181). In the distant future, altered germ lines could protect humans against cancer, diabetes and other age-related problems (180).
   • Mitochondrial replacement therapy: mitochondria contain their own DNA and are present in all somatic cells (outside the nucleus), but are only inherited by egg cells (that is maternal inheritance). This therapy is legal in the United Kingdom to prevent rare genetic diseases. See: Mitochondrial transfer (94), (136), mitochondrial-replacement (142), (147), nuclear transfer, (135), or polar-body transfer (169) to circumvent mitochondrial diseases.
     
     

     Gene therapy techniques More than a thousand proof-of-principle clinical studies have been done around the world, and dozens have shown positive results, but as yet no form of gene therapy has been approved for routine use (81). However, in 2012 European Medicines Agency approved Glybera for the treatment of lipoprotein lipase (LPL) deficiency (104). This is the first gene therapy to be recommended for authorization in the European Union. It is somatic gene therapy, the germline will not be affected. According to the WHO gene therapy holds great promise for treating cystic fibrosis (CF). Others (10) see gene therapy for CF as a failure and invest in phenotypic therapy (!). In general gene therapies for monogenetic disorders other than blood disorders have had limited success so far (12). Gene therapy has shown lasting benefits for the immune systems of a number of children with a rare and fatal immune-deficiency disease (SCID, Wiskott-Aldrich syndrome) (29); patients with β-thalassemia (171), hemophilia B (175), some eye diseases, and a devastating brain disorder called Metachromatic Leukodystrophy (61). Gene therapy aimed at treating muscular dystrophy in the elderly does not affect the next generation. In the future Prenatal Gene Therapy or In utero gene therapy might be possible. Typically, gene transfer into the germline is considered a risk. Genome editing (of human cell lines): targetable nucleases have been used to modify more than 150 human genes and loci. Also treatment of stemcells from a trisomy 21 (Down's syndrome) individual could lead to loss of the entire extra chromosome 21, restoring normal disomy (153). A nuclease has also already entered clinical trials, signaling the beginning of genome engineering as therapy (153). CRISPR-technique: it is already possible with the CRISPR-technique to make precise mutations in multiple genes in mouse embryos (151), (156). Hans Clevers (Hubrecht Institute, Utrecht, the Netherlands) repaired the Cystic Fibrosis gene, CFTR, in cultured intestinal stem cells obtained from CF patients (154). Feng Zhang is interested in using CRISPR to treat neuro­psychiatric conditions such as Huntington’s disease and schizophrenia by repairing genes in human tissues (157). According to Gerald Schatten, new work raises the possibility that CRISPR will one day be used to change the genetic makeup of human embryos (160). Many groups are already using gene-editing tools to develop therapies that correct genetic defects in people (such as by editing white blood cells (179)). However, experts call for a halt in research on DNA modification of human embryos – even for research (178). A problem that should be solved first is: off-target modifications of DNA (that is unwanted, harmful modifications) (189). On December 8 2023 the U.S. Food and Drug Administration approved the first CRISPR treatment for sickle cell disease. (208). Antisense therapy In the future: addressing the genetic cause of Down syndrome by inactivating the extra copy of chromosome 21 (162). Latest news: (145), (146), (153), (171), (172), (175), (183), (184), (185),(190) See also: wikipedia.

     
     
3. Future methods for improving the human genome:
   clean-up (112), delete dispensable DNA sequences (165), edit (126), removal of integrated HIV proviral DNA (166) and repair (133) the human genome; enhancing natural levels of DNA-repair (proofreading); protecting genome integrity by transcriptional silencing of retrotransposons (177). In stead of targeting specific mutations, a more universal method could be to enhance the natural level of DNA-repair (19). All organisms have repair mechanisms, but the bacterium Deinococcus radiodurans, which resembles E. coli in physiological terms, yet has DNA repair mechanisms of far greater efficacy and represents the most radiation-resistant organism known (for example: many 'redundant' copies of the repair-genes plus additional mechanisms that help the repair process). We could learn something from this bacterium and introduce it into the human genome. Another organism with beneficial genes is the tardigrade species Ramazzottius varieornatus which produces a protective protein that provides resistance to damaging X-rays. And researchers were able to transfer that resistance to cultured human cells (194).
   Mutations that are certainly important to prevent are mutations in genes that are involved in DNA replication or repair because they cause mutations in other genes. Furthermore, the germline should be protected from the mutagenic effects of Transposable Elements (LINE-1 and Alu elements) (63). Cellular processes that control retrotransposon activity should be improved (73). Also, prevention of the generation of reactive oxygen species would be useful. And the role of Hsp90 and stress in regulating the integrity of the human genome should be studied. Another target is adding extra copies of anti-cancer gene p53 which seem to prevent cancer in elephants (195). Other solutions which evolution produced in other animals could be applied to humans also (196).
4. The Synthetic Genome:
   In the future a synthetic human genome could be technical possible. In April 2014 scientists reported the Total Synthesis of a Functional Designer Yeast Chromosome (163),(164). In 2016 Jef Boeke et al announced The Genome Project–Write (197), (198). The HGP-Write project will include whole-genome engineering of human cell lines. That means to synthesize the human genome from scratch or: de novo synthesized DNA. Potential benefits include improved cancer resistance, delete potentially deleterious genes such as prion genes, improved genome stability (comprehensively eliminating endogenous repetitive 'selfish DNA' elements), fail-safe security (prevent formation of germ cells, e.g., by removing transcriptional regulators).

1. The main problems are the high spontaneous mutation rate in humans, and
2. the ever decreasing levels of natural selection (caused mainly by medical science)
3. the inescapable result is that our mutational load is increasing
4. we cannot correct this by technological fixes

  Notes  

1. Adam Curtis All watched over by machines of loving grace, part 3.
2. Narrow Roads of Gene Land. The collected papers of W. D. Hamilton. Volume 1-3. W. H. Freeman: Volume 1 Evolution of Social Behaviour (1996), Oxford University Press: Vol 2 Evolution of sex (2001), Vol 3 Last Words (2005) (edited by Mark Ridley).
3. "During the second expedition (...) Bill contracted malaria in the Congo, collapsed with haemorrhaging soon after returning to London, and without fully recovering consciousness a few weeks later, at the age of only 63." (page 445, Narrow Roads Vol 3) (biography by Alan Grafen).
4. On the other hand there is no map of the worldwide distribution of genetic diseases. The UC Atlas of Global Inequality mentions 'Non-communicable diseases' (heart disease and cancer) in the glossary, but there is no map.
5. It is unlikely that national differences in lifespan are genetical. The life expectancy at birth of the world is 67.2 years, from 39.6 (Swaziland =40% below world average!) to 82.6 years (Japan). See: wikipedia. Additionally, changes in lifespan are too fast to be genetical, see: wikipedia. Only a few genetic diseases (Thalassaemia, Sickle cell anemia, Tay sachs disease) have a specific geographic distribution (WHO).
6. David Haig (2003) 'The science that dare not speak its name', Quarterly Review of Biology 78: 327-335. Free pdf. The second part of this review is about eugenics. One of the very few reviews about Hamilton's eugenic views I know of.
7. WHO seems unaware of the dysgenic effects of helping CF patients to become fathers: "CF also can cause reproductive problems - more than 95 percent of men with CF are sterile. But, with new technologies, some are becoming fathers. Although many women with CF are able to conceive, limited lung function and other health factors may make it difficult to carry a child to term." (source). As long as having children is part of the quality of life, the dilemma is unsolved.
8. Tollånes MC, Rasmussen S, Irgens LM. Caesarean section among relatives, Int J Epidemiol. 2008 Dec;37(6):1341-8. Epub 2008 Jun 7. This publication appeared after Hamilton died. Caesarean section rates are increasing: A mother born by caesarean section had a 55% increased risk of having her first child by caesarean section A female-to-female familial predisposition to caesarean section was observed. It could be caused by biologic inheritance, primarily working through maternal alleles and/or environmental factors. The results imply that both mechanisms could be important. Conclusion: "it represents an economic burden to society". So Hamilton was right in that respect.
9. A pair of spectacles is a medical device that prevents natural selection. Just as power-assisted-steering in cars, central heating and air conditioning.
10. Steven Rowe, J.P. Clancy, Eric Sorscher (2011) A Breath Of Fresh Air. Scientific American August 2011. Further: Strachan and Read (2011) state "Until recently, virtually nobody with CF lived long enough to reproduce" (Human Molecular Genetics, p. 88).
11. THE GLOBAL ECONOMIC COST OF CANCER Please compare with costs of tsunami in Japan in 2011.
12. Tom Strachan, Andrew Read (2011) Human Molecular Genetics, p. 712.
13. Verma IM, Weitzman MD. (2005) Gene therapy: twenty-first century medicine. Annu Rev Biochem. 2005;74:711-38.
14. Timothy P. O'Connor & Ronald G. Crystal (2006) Genetic medicines: treatment strategies for hereditary disorders, Nature Reviews Genetics 7, 261-276 (April 2006)
15. Antina de Jong et all (2011) Advances in prenatal screening: the ethical dimension, Nature Reviews Genetics 12, 657-663 (September 2011). The authors discuss 'The autonomy rights of the future child', but this is about individuals and pregnant mothers, and is not generalized to the human genome of the future.
16. "I predict that in two generations the damage being done to the human genome by the ante- and postnatal life-saving efforts of modern medicine will be obvious to all and be a big taling point of science and politics." (Vol 2, xlvii, Preface).
17. It would be wrong to say that the WHO is unaware of genetic diseases. See table: (data added from other sources)
    
    

    genetic condition	estimated number of cases
    data from Genes and human disease (WHO).
    Down Syndrome	Each year approximately 3,000 to 5,000 children are born. [Affects 1 in about 700 individuals]
    Thalassaemia	Iran: about 8,000 pregnancies are at risk each year. "Worldwide, an estimated 63,000 children a year are born with β-thalassemia, most of them in Southeast Asia and the Mediterranean" (139).
    Sickle cell anemia	millions
    Haemophilia	5400 people in the UK with haemophilia A and about 1100 with haemophilia B
    Cystic Fibrosis	European Union 1 in 2000-3000 new borns is found to be affected by CF. Affects about 30,000 people in the United States. Carrier frequency is about 1/25
    Tay sachs disease	from 1 : 27 to 1 : 250
    Fragile X syndrome	1 in 3600 males and 1 in 4000 to 6000 females with full mutation worldwide
    Huntington's disease	about 5 - 7 people per 100,000
    Cancer	over 4.2 million deaths
    Diabetes	about 180 million 25.8 million children and adults in the United States (8.3% of the population) have diabetes.
    Cardiovascular Disease	16.6 million deaths
    Asthma	20.3 million people currently have asthma
    data from other sources:
    Angelman syndrome	1 in 15,000 live births (77) or about 66 per million live births
    retinitis pigmentosa	About 100,000 people in the U.S. have a form of retinitis pigmentosa (source)
    Genetic disorders of children	approximately 500,000 children in Canada (source)
    Pompe disease	estimated at 1 in every 40,000 births (source)
    MCAD deficiency	estimated 1 in 17,000 people (USA) (more common in Europe), treatable with diet (source)
    mitochondrial respiratory chain disorders	at least 1 in 5,000 live births (Skladal, Halliday, Thorburn 2003)
    mitochondrial diseases	1 in 200 (HFEA); 1 in 5,000 (R. H. Haas, 2007); 1 in 4,000 children in the US develop mitochondrial disease (wiki). 1 in 200 children born each year have mutations in the mitochondrial DNA; 1 in 6,500 individuals, mitochondrial disease causes serious and often fatal conditions, which include blindness, muscular weakness, and heart failure (BioEssays 2015 Vol 37 Issue 6).
    Fanconi anaemia	1 in every 100,000 births. Genetically heterogeneous: 15 genes mutated (134).
    Alpha-1 antitrypsin deficiency	In the UK it is estimated that 1 person in 3,000-5,000 has A1AT deficiency. (source)
    Blue Cone Monochromacy	a rare genetic X-linked retinal disorder that affects 1 to 50 males in 100.000.
    Duchenne Muscular Dystrophy	affects approximately 1 in 3500 boys (172)
    Rett syndrome	affects approximately one in every 10-12,000 females and is only rarely seen in males. De novo mutation in MECP2 gene, X-chromosome

    
    
    WHO Summary:
    - 7 million children around the world are born annually with severe genetic disorders or birth defects.
    - 90% of infants born with genetic disorders are found in developing countries, contributing significantly to global child mortality. (factsheet Human Genetics programme WHO). I did not find the economic burden of genetic disorders. Disabilities is reported but not genetic. Here is information from the WHO: Amniocentesis and chorionic villus sampling for prenatal diagnosis.
18. Apart from Alan Grafen and David Haig, nobody discusses the eugenic views of Hamilton. For example the encyclopadic Evolution: The First Four Billion Years edited by Michael Ruse, does contain an entry about Hamilton written by Marlene Zuk, but nothing about eugenics. The Wikipedia article mentions eugenics without explaining. The eugenics wikipedia article does not mention Hamilton (assessed aug 2011).
19. We can learn from patients with DNA repair-deficiency disorders.
20. "...it is obvious that each wheelchair or bed-bound victim must add to the burden of those fit and tax-paying individuals who ultimately have to provide for them to survive". p.475 Vol 2 Narrow Roads. (Not completely true, because there is also money from charity.)
21. Exceptions: there is not always a sharp boundary between genetic and non-genetic diseases. For example, the cause of asthma may include: genetic heredity, lifestyles, smoking, pollution, and viral infections.
22. In my country the government does economize on special education, for example for children with learning disabilities such as dyslexia. Dyslexia is partly genetic (source). Also reduction of money going to the support of mentally handicapped people. See also: Tulisa: My Mum and Me about parents with mental health problems. US: US President Barack Obama proposed a US$664-million cut in congressional funding for the US Centers for Disease Control and Prevention (CDC) in his 2013 budget request. See also note 106.
23. Discharges from pharmaceutical factories contaminate rivers on three continents (Nature 18 Aug 2011).
24. Here is a very impressive, extensive overview of NIH-funding per type of disease per year (2007-2012). Please note that the categories: Gene Therapy, Gene Therapy Clinical Trials, Genetic Testing, Genetics together have a budget of 8,1 billion dollars (Estimated 2012). This is apart from the vague category 'Clinical Research' the biggest budget! One has to add many diseases listed with a genetic basis. Then there is 'economic damage' of disease, which is not included. For example: "Schizophrenia alone costs the United States tens of billions of dollars each year." (Nature 27 Oct 11). 27 Oct 2011
25. About 3% of Down syndrome cases are heritable (familial Down syndrome). Since most cases of Down are not hereditary, eugenics does not make sense. An increase in life expectancy by better medical care is not an eugenic problem because most Down syndrome patients are infertile.
26. Those who think Hamilton is exceptionally, consider that "between 2 and 3 million unwanted dogs are euthanized in animal shelters each year" and "in 1970, 23 million dogs and cats were euthanized in animal shlters in the United States" according to Hal Herzog (2010) 'Some we love, some we hate, some we eat'.
27. Thomas R. Insel (2008) Assessing the Economic Costs of Serious Mental Illness, American Journal of Psychiatry 165:663-665, June 2008 (editorial):
    "Unlike other medical disorders, the costs of mental disorders are more "indirect" than "direct." The costs of care (e.g., medication, clinic visits, or hospitalization) are direct costs. Indirect costs are incurred through reduced labor supply, public income support payments, reduced educational attainment, and costs associated with other consequences such as incarceration or homelessness. Another kind of indirect cost results from the high rate of medical complications associated with serious mental illness, leading to high rates of emergency room care, high prevalence of pulmonary disease (persons with serious mental illness smoke 44% of all cigarettes in the United States), and early mortality (a loss of 13 to 32 years)", "The $317 billion estimated economic burden of serious mental illness excludes ...". Please note: the author talks about more efficient treatment, but it never occurs to him that the real problem is the degenerating human genome.
28. Brain burdens, Nature 477, 132 08 September 2011. "A good measure of disease burden is the disability –adjusted life year (DALY) – the person-years lost in a population owing to disability and shortened life. The authors establish brain disorders – both mental and neurological – as the greatest health burden on the population, comprising 23.4% of all DALYs among men and 30.1% for women". The bad news is that the Nature article does not discuss what the genetic contribution to mental disorders is, in other words: the eugenic problem. 8 Sep 2011
29. Long-term fix for SCID kids, Nature 477, 8-9 01 September 2011. 8 Sep 2011
30. The reason for artificial insemination is not always infertility, another reason is that more women choose to have babies on their own. "No one knows how many children are born in this country [USA] each year using sperm donors. Some estimates put the number at 30,000 to 60,000, perhaps more" (nytimes). Young adults born by AI are worried about unknowingly having children with a AI half-brother or -sister, and they are worried about having children with genetic diseases, but eugenic worries are not yet among them. The eugenic worries are: (1) natural selection on the natural form of coitus is eliminated, and this could result in disappearance of for example orgasm; (2) infertility is transmitted to the next generation. Potentially, AI could have positive eugenic effects if donors are selected for good health 11 Sep 2011
31. European Science Foundation (2010) 'Male Reproductive Health. Its impacts in relation to general wellbeing and low European fertility rates', Sep 2010. "It has been estimated that more than 7% of all children born in 2007 in Denmark were conceived by use of ART, which includes in vitro fertilisation, intracytoplasmic sperm injection (ICSI), and intrauterine insemination". Remarkably, altough the ESF is worried: "Dependency on ART would dramatically influence society, since only limited resources are available for state-supported healthcare" (p. 3), they seem only worried about who is going to pay for ART, not about the dysgenic effects of ART itself. The ESF ascribes the increasing use of ART to preventable environmental causes of infertility (because the increase is too rapid to be genetic). On page 7 the report says: "It will be of great importance to ensure that the sperm used for ICSI or IVF procedures is as well selected in terms of DNA integrity as under natural conception" which seems to show eugenic awareness, but they fail to explain how to ensure genetic integrity of sperm of men with fertility problems. Furthermore, since their goal is to treat male reproductive disorders (p. 7), which is dysgenic, I doubt whether they are fully aware of the eugenic problems of ART.
32. Dudley Kirk (1966) 'Demographic factors affecting the opportunity for natural selection in the United States', Biodemography and Social Biology, Volume 13, Issue 3, 1966. "This amazing reduction in mortality, clearly due to environmental factors, has given rise to concern that relaxation of selective pressures may be enabling the survival of the unfit and deterioration of the genotype". Also published in: Eugenics quarterly. 13 (3): 270-273; 1966.
33. Scott Freeman and Jon Herron (2007) Evolutionary Analysis has a very good section on 'Compulsory sterilization' starting on page 208.
34. Ariel Fernández, Michael Lynch (2011) Non-adaptive origins of interactome complexity, Nature 474, 502-505 (23 June 2011)
35. Germline therapy is very risky because an error is propagated to all future generations. Therefore, it has not been done in humans. For a discussion see Box 21.6 'The ethics of germ-line gene therapy' in 12. In the mouse a human artificial chromosomes (HAC) has been successfully used to deliver the gene Duchenne muscular dystrophy (DMD) to muscle cells. Hamilton was very sceptical about HACs. Source: Francesco Saverio Tedesco (2011) Stem Cell–Mediated Transfer of a Human Artificial Chromosome Ameliorates Muscular Dystrophy, Sci Transl Med 17 August 2011: Vol. 3, Issue 96, p. 96ra78.
    A defense of germline therapy: Letters: Henry I. Miller (2015) Germline gene therapy: We're ready, Science 19 Jun 2015.
36. In general: if basic processes in the early embryo such as DNA replication and ATP synthesis are damaged by mutation the embryo dies, which is natural selection. Only embryos with low reactive oxygen species (ROS) leak make it through embryonic development (Nick Lane, 2011). One woman lost six children to a mitochondrial disease within two days of birth. Her seventh and last child died, aged 21. This is natural selection. Examples of untreatable genetic diseases in children: Lafora disease (Most patients with this disease do not live past the age of twenty-five). 4 Mar 2015. Progeria is an extremely rare genetic disorder wherein symptoms resembling aspects of aging are manifested at a very early age; as there is no cure, few people with progeria exceed 13 years of age. Duchenne muscular dystrophy (DMD) is a fatal muscle disease affecting 1 in 3500 to 5000 boys; cardiomyopathy and heart failure are common, incurable, and lethal consequences of DMD. The average life expectancy for individuals afflicted with DMD is around 25. 22 Jan 2016. People with type 1 diabetes have traditionally lived shorter lives, with life expectancy having been quoted as being reduced by over 20 years (192).
37. Genetic Heterogeneity of Deafness, Marriages among the Deaf (Gallaudet University) 18 Sep 2011
38. James F. Crow (1997) The high spontaneous mutation rate: Is it a health risk? PNAS August 5, 1997. This free article is based on a public lecture of population geneticist James Crow at the National Academy of Sciences, November 14, 1996. It is an important article. It is about eugenics without mentioning the word. He concludes:

    "I do regard mutation accumulation as a problem. It is something like the population bomb, but it has a much longer fuse. We can expect molecular techniques to increase greatly the chance of early detection of mutations with large effects. But there is less reason for optimism about the ability to deal with the much more numerous mutations with very mild effects. But this is a problem with a long time scale; the characteristic time is some 50–100 generations, which cautions us against advocating any precipitate action. We can take time to learn more. Meanwhile, we have more immediate problems: global warming, loss of habitat, water depletion, food shortages, war, terrorism, and especially increase of the world population. If we don't somehow reduce the global birth rate to a sustainable level commensurate with economic viability, we won't have the luxury of worrying about the mutation problem."

    Crow recognizes that for the past few centuries natural selection has been greatly reduced in wealthy nations by 'rapid environmental improvements'. As a consequence harmful mutations have been accumulating. Crow is especially worried about the numerous mutations with very mild effects. This results in health risks (headaches, stomach upsets, depressed periods). But humans can improve their environment, so mutations are masked. But this depends on wealth. What if we can't afford it economically anymore? These are essentially Hamilton's worries! Crow certainly is worried about the future of the human genome, and he would reduce the mutation rate to zero if he could. However, he does not specify the causes that reduce natural selection. So, the dilemma of Janus-faced modern medicine is completely out of his sight. Also, he thinks that mutations are a problem of the far future. The word 'spontaneous' in the title is a little misleading if the problem is caused by improved medical technology. I agree with his statement about the more immediate problems. 21 Sep 2011.
    Alexey Kondrashov (2012) shows that Crow shares Hamilton's worries ('due to advances in medicine'!):

    "Crow was very concerned about the negative impact on human health of mildly deleterious alleles that, due to advances in medicine, can accumulate almost unchecked by natural selection. Individually, these may do little – causing a slight increase in blood pressure, for instance. But cumulatively their effect could prove fatal. Unlike some other prominent geneticists, Crow was always careful to separate science and policy and never advocated simplistic approaches to dealing with this problem." Alexey Kondrashov (2012) 'James Crow (1916–2012)', Nature, 481, 444 26 January 2012.

39. David N. Cooper et al (2010) Genes, Mutations, and Human Inherited Disease at the Dawn of the Age of Personalized Genomics, Human Mutation, Vol. 31, No. 6, 631–655, 2010. 21 Sep 2011
40. Prader-Willi syndrome: boys have a very small penis; may be corrected with testosterone. Low levels of sex hormones may be corrected at puberty with hormone replacement (source). No discussion of the possibility that successfull treatment could enable patients to have children. 22 Sep 2011.
41. "Tumours removed, joints replaced, organs transplanted: every weekday, 85,000 non-emergency operations take place in the United States alone", review of Invasion of the Body: Revolutions in Surgery, Nature 22 Sep 2011. 22 Sep 2011
42. "Scientists have begun to overhaul a yeast's genome to make it more stable, engineerable and evolvable. Remarkably, the part-natural, part-synthetic yeast cells function and reproduce without obvious ill effects". Nature 477, 413–414 22 Sep 2011
43. A few HIV-infected individuals (dubbed 'elite neutralizers') do develop antibodies that potently nullify diverse HIV-1 strains. So, if this has a genetic basis, these individuals are genetically immune to HIV and can be expected to survive HIV and have children. Nature 22 Sep 2011.
44. Jon W. Gordon (1999) Genetic Enhancement in Humans, Science Vol. 283 no. 5410 pp. 2023-2024 26 March 1999. 22 Sep 2011. Gordon has a very pessimistic view about genetic enhancement: "Thus, any effort to enhance the human species experimentally would be swamped by the random attempts of Mother Nature.". When applied to evolution it would follow that no positive mutation could become fixed in the population and the theory of evolution would be undermined. 27 Sep 2011
45. In the Netherlands neonatologists do not treat premature babies born before the 26th week, in other countries neonatologists treat premature babies of 23 - 24 weeks. 25 Sep 2011.
46. The discovery of antibiotics is more than 70 years ago. This is about 2 - 3 generations. Therefore, the evolutionary effect on the human genome will be very small. However, the effect on the genomes of microbes is very strong (antibiotic resistance!). 26 Sep 2011
47. The field of genetic counseling is too complex to summarize here. A few notes: Genetic counseling can have eugenic effects or it could have exactly the opposite effect according to Walter Fuhrmann and Frierich Vogel (1983) Genetic Counseling Third Edition, p.162. 26 Sep 2011. Peter Harper and Angus Clarke (1997) Genetics, Society and Clinical Practice, distinguish two main paradigms of prenatal screening: 'genetic cleansing' ("aimed at preventing the birth of affected individuals in the most cost-effective manner" which could be said to be eugenic); and 'informed choice' ("aimed at maximizing client autonomy by facilitating informed choice") (p. 125). 27 Sep 2011
48. Cost-effectiveness: the costs of screening and early treatment of newborns are less than no screening and late treatment of the disease. Hamilton would have dismissed this as dysgenic, I suppose, because the individual is treated somatically. Prenatal screening could be eugenic. The literature on cost-effectiveness is vast. For criticism see: T. G. Ganiats (1996) Justifying prenatal screening and genetic amniocentesis programs by cost-effectiveness analyses: a re-evaluation, Med Decis Making 1996 Jan-Mar;16(1):45-50. 28 Sep 2011
49. Julian s. Huxley (1936) 'Eugenics and Society', reprinted in: Carl J. Bajema (1976) Eugenics Then and Now:

    "But in civilized human communities of our present type, the elimination of defect by natural selection is largely (...) rendered inoperative by medicine, charity, and the social services. (...) The net result is that many deleterious mutations can and do survive." (p.263)

    Hamilton would agree. 28 Sep 2011
50. H. J. Muller wrote many eugenic articles (largely ignored in wikipedia), see: Carl J. Bajema (1976) Eugenics Then and Now. Famous is his 1949 article: 'Our Load of Mutations' (not mentioned in wikipedia). 28 Sep 2011
51. Monroe Strickberger (2000) Evolution, third edition, p.617-628 and fourth edition (2008). (good discussion of eugenics) 28 Sep 2011
52. Essential medicines: drugs needed to satisfy all basic human needs. This is similar to 'essential amino acids'. However, essential medicines are worrying: it means we are all sick and cannot live without medicines. The number of drugs on the WHO list of essential medicines has nearly doubled, from 186 in 1977 to 320 in 2002. The increase is worrying too. 29 Sep 2011
53. Randolph Nesse, George Williams (1996) Why we get sick (see here) are clearly against eugenics, but are also blind to the degeneration of the human genome and the possible role of modern medicine in that process. Examples: treatment of PKU (p.106), "injections of extra oxytocin have stopped excessive bleeding and saved thousands of lives" (p.201) (my empahsis). It does not occur to them that treatment prevents natural selection. 1 Oct 2011
54. Armand Leroi (2006) The future of neo-eugenics, EMBO reports (2006) 7, 1184 - 1187. 2 Oct 2011 See also his book Mutants. On Genetic Variety and the Human Body (2003): "our health and happiness are being continually eroded by an unceasing supply of genetic error." (page 18). 18 Oct 2011
55. Lisenka E L M Vissers et al (2010) A de novo paradigm for mental retardation, Nature Genetics 42, 1109–1112 (2010): "The per-generation mutation rate in humans is high." 4 Oct 2011
56. Spina Bifida. Economic Cost (CDC). See also Birth Defects page. (5 Oct 2011)
57. David B. Goldstein (2011) Growth of genome screening needs debate, Nature 476, 27–28 (04 August 2011) (5 Oct 2011)
58. C. J. Bell et al Carrier testing for severe childhood recessive diseases by next-generation sequencing, Sci Transl Med. 2011 Jan 12 (5 Oct 2011)
59. Kerri Smith (2011) Trillion-dollar brain drain, Nature News 6 Oct 2011 (6 Oct 2011)
60. I found this also in John Harris (2007) Enhancing Evolution. The ethical case for Making Better People, p. 79. However, I don't like 'Making Better People' and 'enhancing', we are only in the phase of correcting errors in DNA. Otherwise, recommended reading. (8 Oct 2011)
61. Jocelyn Kaiser (2011) Gene Therapists Celebrate a Decade of Progress, Science 7 October 2011 (9 Oct 2011)
62. The World Health Organization (WHO) lists indoor air pollution (IAP) from primitive household cooking fires as the leading environmental cause of death in the world, as it contributes to nearly 2.0 million deaths annually –more deaths than are caused each year by malaria. (14 Oct 2011)
63. Sergio Lukic, Kevin Chen (2011) Human piRNAs Are Under Selection in Africans and Repress Transposable Elements, Mol Biol Evol (2011) 28 (11): 3061-3067 (24 Oct 2011)
64. Eleanor Raffan, Robert K. Semple (2011) Next generation sequencing–implications for clinical practice, Br Med Bull (2011) 99 (1): 53-71.
    "Stephen Kingsmore at Children's Mercy Hospital in Kansas City, Missouri, argues that clinical sequencing should be limited in scope. He advocates sequencing just what he calls the Mendelianome, the genetic regions known to be involved in inherited diseases. His group is developing methods that use a panel of mutations associated with just over 600 recessive diseases for such screening." Brendan Maher (2011) Human genetics: Genomes on prescription, Nature 478, 22-24 (2011). (7 Nov 2011)
65. ICSI is most commonly used to overcome male infertility, was developed in Vrije Universiteit Brussel, Belgium. It is claimed that until 2012 2 million children are born with ICSI. There is a Y-chromosome deletion causing almost complete infertility. This infertility is bound to be passed from father to son (!). However, it is treatable by surgically extracting sperm and micro-injecting it into an egg. This acts strongly against natural selection. Source: Alan Handyside (2010) Let parents decide, Nature 464, 978–979 (15 April 2010) (31 Oct 2011)
66. However, the resolution of techniques to detect genomic aberrations are becoming better. Array-comparative genomic hybridization begins to look like a genomic Maxwell's Demon. (31 Oct 2011)
67. Karen Weintraub (2011) The prevalence puzzle: Autism counts, Nature 479, 22–24 (2011) (3 Nov 2011)
68. Laurent Mottron (2011) Changing perceptions: The power of autism, Nature 479, 33–35 (3 Nov 2011)
69. Recurrent Early Pregnancy Loss, Genetic Causes - Genetic Abnormalities/Mendelian Disorders, Medscape Reference. (10 Nov 2011)
70. Medical system in crisis as thousands of doctors leave the country (04.10.11) (14 Nov 2011)
71. Egbert R. te Velde, Peter L.Pearson (2002) The variability of female reproductive ageing, Human Reproduction Update, Vol.8, No.2 pp. 141–154, 2002. "the frequency of chromosome abnormalities at conception can be expected to rise rapidly with increasing maternal age, such that the majority of embryos are chromosomally abnormal in women approaching 40 years old." (14 Nov 2011)
72. Thomas B. L. Kirkwood, Steven N. Austad (2000) Why do we age? Nature 408 9 November 2000 (14 Nov 2011)
73. "Examples of human genetic disorders caused by de novo L1, Alu and SVA insertions continue to accumulate, and 65 cases have been shown to cause heritable diseases, such as haemophilia, cystic fibrosis, Apert syndrome, neurofibromatosis, Duchenne muscular dystrophy, β-thalassaemia, hypercholesterolaemia and breast and colon cancers", from: Richard Cordaux, Mark A. Batze (2009) The impact of retrotransposons on human genome evolution, Nature Reviews Genetics 10, 691-703 (October 2009). (28 Nov 2011)
74. Michel Tibayrenc (editor) (2011) Genetics and Evolution of Infectious Diseases, Elsevier. (9 Dec 2011)
75. R. Dolin (2009) Swine (H1N1) Flu: How to understand your risk and protect your health (Harvard Health Publications, 2009).
76. Christine Junge (2011) Morbidity: A personal response, Nature 480, S14–S15 (08 December 2011)
77. Greg Miller (2011) New Hope for a Devastating Neurological Disorder, Science 23 December 2011.
    Wikipedia: "Sexual development is thought to be unaffected, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome", "General health is fairly good and life-span near average."
78. Gapminder world: life expectancy and total health spending (US$) per person per country.
79. rivm: More than a fifth of all costs were spent on mental disorders. This amounts to 15.9 billion euro. A breakdown to specific diseases reveals that mental retardation and dementia are the most expensive single conditions, with 5.6 and 3.5 billion euro. (28 dec 2011)
80. Ewen Callaway (2012) UK sets sights on gene therapy in eggs, Nature News 24 January 2012
81. Alison Abbott (2012) French institute prepares for gene-therapy push, Nature News 25 January 2012
82. Jocelyn Kaiser (2012) New Cystic Fibrosis Drug Offers Hope, at a Price, Science 10 Feb 2012. About the costs: "As more such costly drugs emerge, "there's going to have to be a reality check," Francis Collins says. He anticipates a 'complicated conversation' between companies, insurers, and 'society as a whole' to make the drugs an affordable part of health care."
83. Genetics of Diabetes. The proportion of heritability explained for Type 1 diabetes: ~60% and Type 2 diabetes 20–25% (Eric S. Lander (2011) Initial impact of the sequencing of the human genome, Nature, 470, 187–197 ). See also: The Genetic Landscape of Diabetes.
84. The problem of the human genome is recent. Analysis of data from the HapMap has revealed at least 300 genomic regions that have been under positive selection during the past ~5,000–30,000 years. In Europe, powerful selection around the dawn of agriculture favoured a regulatory variant that causes lifelong expression of lactase, the enzyme required to digest milk; a similar mutation was independently selected in cattle-herding groups in East Africa. In West Africa, strong selection for a gene encoding a receptor for the Lassa fever virus may indicate a resistance allele. Tibetans, a population living at 14,000 feet, and Han Chinese are closely related, but show striking population differentiation at a locus encoding a protein involved in sensing oxygen levels. (Eric S. Lander (2011) see above )
85. G. Kosova et al (2010) The CFTR Met 470 Allele Is Associated with Lower Birth Rates in Fertile Men from a Population Isolate, PLOS Genetics.
86. Daniel G. MacArthur et al (2012) A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes, Science 17 February 2012.
87. Lluis Quintana-Murci (2012) Gene Losses in the Human Genome, Perspective article, Science 17 February 2012.
88. Jocelyn Kaiser (2012) The Case of the Missing Genes, Science Now 16 February 2012: "They found that 1285 loss-of-function gene variants are likely genuine, about 100 of which appear in the genome of the average European, MacArthur's team reports today in the 17 February issue of Science. Some are mutations in known disease-causing genes and occur in only one copy of the gene, so the person's other copy probably compensates. But the average individual had lost both copies of roughly 20 genes, which means the gene is essentially missing–a surprisingly high number, MacArthur says. Many of these genes probably don't affect health, and his team's analysis suggests that lacking some genes might even be beneficial." 17 February 2012
89. Ewen Callaway (2012) 'Gene hunt is on for mental disability', Nature, 19 Apr 2012. Also published in Scientific American (free).
90. Michael Lynch (2010) Rate, molecular spectrum, and consequences of human mutation, PNAS. Important article. Agrees with Hamilton about cultural causes of relaxation of natural selection and the resulting accumulation of mutations, but does not mention Hamilton.
91. Amy Maxmen (2012) The hard facts, Nature 31 may 2012.
92. The Innovative Medicines Initiative, a joint venture between the European Union and Europe's pharmaceutical industry, last week launched a new €220 million collaboration of companies and public partners to combat antimicrobial resistance. (Science 1 Jun 2012)
93. Callum J. Bell (2012) Carrier Testing for Severe Childhood Recessive Diseases by Next-Generation Sequencing, Sci Transl Med 12 January 2011: "In summary, a technology platform for comprehensive preconception carrier screening for 448 recessive childhood diseases is described. Combining this technology with genetic counseling could reduce the incidence of severe recessive pediatric diseases and may help to expedite diagnosis of these disorders in newborns."
94. Bioethics board backs embryo alteration for mitochondrial disease, Nature News Blog 11 Jun 2012. (about the prevention of mitochondrial diseases such as some forms of muscular dystrophy and neurodegenerative disorders). see also: Mitochondrial Transfer Technology Could Reduce Risk of Childhood Disease (October 25, 2012)
95. To give just one example: "The Wellcome Trust has now awarded Turnbull £4.4 million (US$6.8 million), which his university has topped up with another £1.4 million, to perform the procedures on healthy human eggs" [nuclear transfer procedures]. (Ewen Callaway, Nature 24 January 2012). In unassisted natural human reproduction the creation of a human embryo is free.
96. "The tests can spot genetic abnormalities, such as those that cause Down's syndrome, as early as ten weeks after conception – several weeks sooner than tests already in use". Erika Check Hayden in Nature 27 Jun 2012. (the tests are non-invasive and will in the near future to sequence a complete fetal genome).
97. Alison Motluk (2012) Fetal genome deduced from parental DNA, Nature 6 June 2012 (Nature News)
98. Jacob A. Tennessen et al (2012) Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes, Science 6 July 2012.
99. So I. Nagaoka, Terry J. Hassold, Patricia A. Hunt (2012) Human aneuploidy: mechanisms and new insights into an age-old problem, Nature Reviews Genetics 13, 493-504 (July 2012).
100. Interestingly, there is a direct relation with the quality of a health care system. The death rate for women giving birth plummeted in the 20th century (wikipedia) clearly showing the effects of health care. This means that natural selection still exists but has decreased very substantially.
101. Eric M Poolman and Alison P Galvani (2007) Evaluating candidate agents of selective pressure for cystic fibrosis. ("we conclude that only tuberculosis resistance would have been a sufficient source of selective pressure to result in modern CF incidences").
102. "our finding that negative selection is less effective at removing slightly deleterious alleles from European populations": Kirk E. Lohmueller et al (2008) 'Proportionally more deleterious genetic variation in European than in African populations, Nature 451, 994-997 (21 February 2008)
103. H. Christina Fan et al (2012) Non-invasive prenatal measurement of the fetal genome, Nature, 487, 320–324 (19 July 2012): "Non-invasive determination of the fetal genome may ultimately facilitate the diagnosis of all inherited and de novo genetic disease." Remarkably, they exclusively position their technique as a tool for therapy, not for prevention. That means non-eugenic or anti-eugenic goals.
104. EMA: European Medicines Agency recommends first gene therapy for approval, Press release 20/07/2012: "Gene therapy medicines have the potential to cure genetic disorders by replacing a defective gene with a working copy, thus helping the body to recover functionality". Please note that "to cure genetic disorders by replacing a defective gene with a working copy" does not mean that the genetic mutation in the germline is replaced, so the children of the cured patient will inherit the defective gene. So, one could even argue that this kind of gene therapy is not good for the future of the human genome.
105. Monya Baker (2012) Contest to sequence centenarians kicks off, Nature, 23 Jul 2012. Error rate: with less than one error per million base pairs?
106. On 29 Jul 2012 the official recommendation by CVZ in the Netherlands was made public that medicines for Pompe and Fabry disease will no longer be paid by the health insurance. In 2010 in the Netherlands 55 million euro was spend on therapy for patients with Pompe and Fabry disease (source). Other hereditary diseases with expensive medicines are: Hunter syndrome, Maroteaux-Lamy syndrome, Gaucher syndrome.
107. Joris A. Veltman & Han G. Brunner (2012) De novo mutations in human genetic disease Nature Reviews Genetics 13, 565-575 (August 2012).
108. A definition of "liberal eugenics" is quoted in chapter 4 ('Old Eugenics and the New') of The Case against Perfection of Michael Sandel (2007) as "noncoercive genetic enhancements that do not restrict the autonomy of the child" (p. 75). The book of Sandel is recommended (good reading).
109. Quality-Adjusted Life Year: a QALY gives an idea of how many extra months or years of life of a reasonable quality a person might gain as a result of treatment.
110. Augustine Kong et al (2012) Rate of de novo mutations and the importance of father's age to disease risk, Nature, 23 Aug 2012.
111. Alexey Kondrashov (2012) The rate of human mutation, Nature, 23 Aug 2012
112. Nóbrega (2012) Megabase deletions of gene deserts result in viable mice.
113. CVZ: veel meer dure medicijnen onder de loep Volkskrant 15 sep 2012
114. James X Sun et al (2012) A direct characterization of human mutation based on microsatellites: "We infer that the sequence mutation rate is 1.4–2.3 × 10^–8 mutations per base pair per generation (90% credible interval)".
115. Hans-Ulrich Wittchen (2012) The Burden of Mood Disorders, Science 5 October 2012.
     "the prevalence of mood disorders has remained steady at approximately 10% of the population. ... Mood disorders are dominated by indirect costs such as sick days, unemployment, long-term disability, and suicide attempts."
116. Carol Jean Saunders (2012) Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units, Sci Transl Med 3 October 2012. is intended to be a prototype for use in neonatal intensive care units.
117. Elizabeth H. Blackburn (2012) Telomeres and adversity: Too toxic to ignore, Nature, 490, 169–171 (11 October 2012)
118. Ann Gibbons (2012) Turning Back the Clock: Slowing the Pace of Prehistory, Science 12 October 2012. That would mean 37–38 new mutations per newborn (?), which would be lower than other calculations.
119. Gopa Iyer et al (2012) Genome Sequencing Identifies a Basis for Everolimus Sensitivity, Science 12 October 2012
120. Jennifer Couzin-Frankel (2012) New Company Pushes the Envelope on Pre-Conception Testing, Science 19 October 2012. "Initially, the company will focus on at least 100,000 genetic variants linked to rare recessive and other single-locus diseases"
121. GenePeeks: is a genetic information company with a mission to help families protect the next generation
122. California Cryobank: a large sperm bank headquartered in Los Angeles, follows guidelines of the American College of Medical Genetics and Genomics, which recommends that anyone planning a pregnancy be tested to see if they carry mutations for cystic fibrosis, spinal muscular atrophy, or eight other diseases in a panel associated with Ashkenazi Jewish ancestry.
123. Non-Invasive Prenatal Testing (NIPT) Factsheet, from the National Coalition for Health Professional Education in Genetics. (non-invasive for the fetus).
124. Jaime S. King (2012) Genetic tests: Politics and fetal diagnostics collide, Nature, 1 Nov 2012
     Worldwide, nearly 50 companies are now developing NIPT products.
125. Brian Owens (2012) Genomics: The single life, Nature, 1 Nov 2012
126. Victoria M. Bedell et al (2012) In vivo genome editing using a high-efficiency TALEN system, Nature, 1 Nov 2012
127. Han G. Brunner (2012) The Variability of Genetic Disease, The New England Journal of Medicine 2012; 367:1350-1352 October 4, 2012
128. Matthew Hurles (2012) Older males beget more mutations, Nature Genetics, 44, 1174–1176 (2012)
129. Catarina D Campbell et al (2012) Estimating the human mutation rate using autozygosity in a founder population, Nature Genetics, 44, 1277–1281 (2012): "We estimated an SNV mutation rate of 1.20 × 10^–8 mutations per base pair per generation".
130. Natasha Gilbert (2012) Drug-pollution law all washed up, Nature News 21 Nov 2012
131. Anver Kuliev (2012) Practical Preimplantation Genetic Diagnosis, second edition, Springer. Link gives free materials.
132. Gerald R. Crabtree (2012) Our fragile intellect (I and II), Trends in Genetics, 13 November 2012, Forum: Science & Society.
     "These changes in IQ scores are probably linked to environmental influences including reduction in lead and other heavy metals used in gasoline and paint and the virtual elimination of hypothyroidism in children due to the widespread use of iodinated salt. These and many other advances in prenatal care and prevention of anoxia during childbirth have clear effects on our average intellectual abilities."
133. Elizabeth Pennisi (2012) The Tale of the TALEs, Science 14 Dec 2012
     At least one biomedical team wants to harness the TALE technology to treat human disease, specifically sickle cell anemia. ... Veit Hornung plans eventually to make a TALEN to target every human gene. ... Initial, ongoing clinical trials are already testing the potential to cure HIV infections by using zinc finger nucleases to knock out the gene for the T cell receptor that the virus uses to get into the cell. At the Society for Neuroscience meeting in New Orleans this October, Sangamo scientists also described progress using zinc finger technology to knock out just the mutant version of the Huntington's disease gene, while leaving the other, normal copy of the gene intact.
134. Rosenberg, P. S., Tamary, H. & Alter, B. P. 'How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi anemia in the United States and Israel'. Am. J. Med. Genet. A 155A, 1877–1883 (2011).
135. Daniel Paull, et all (2013) Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants, Nature.
136. Masahito Tachibana, et al Towards germline gene therapy of inherited mitochondrial diseases, Nature 493, 627–631 (31 January 2013)
137. Mark D. Kilby, Anthony Johnson, Dick Oepkes (Editors) (2013) Fetal Therapy: Scientific Basis and Critical Appraisal of Clinical Benefits [Hardcover].
138. Examples incurable genetic diseases:
     • Tay-Sachs disease: Even with the best care, children with infantile Tay–Sachs disease die by the age of 4.
     • Children with Hutchinson-Guilford progeria syndrome (HGPS) manifest accelerated aging symptoms, including failure to thrive, hair loss, joint ailments, lipodystrophy, and cardiovascular disease, typically dying from the latter in their mid-teens.
     • Krabbe disease is an inherited, often fatal disorder affecting the central nervous system. Krabbe disease affects about 1 in every 100,000 people in the United States. Most children who develop Krabbe disease in infancy die before the age of 2 years old (source).
     • Leigh's disease (Leigh syndrome): the prognosis is poor. Individuals who lack mitochondrial complex IV activity and those with pyruvate dehydrogenase deficiency tend to have the worst prognosis and die within a few years. Rate of progression varies, but death typically occurs by 6 to 7 years of age (176)
     • Duchenne Muscular Dystrophy: death of DMD patients usually occurs by age 25, typically from breathing complications and cardiomyopathy. No curative treatment exists. (172)
     • prion diseases: the group of neurodegenerative disorders known as transmissible spongiform encephalopathies or prion disease are incurable and lethal. There are currently no treatments or cures for transmissible spongiform encephalopathies June 2015
     • Gaucher's disease: children with acute neuronopathic Gaucher's disease rarely live past two years. However, fetal gene therapy experiments have been done. Jul 2018
139. Mara Hvistendahl (2013) China Heads Off Deadly Blood Disorder, Science 10 May 2013. "The whole public health care system of Cyprus was nearly collapsing under the burden of treating patients. ... According to the provincial health department, Guangxi has slashed its rate of birth defects from 21.648 per 1000 births in 2008 to 12.79 in 2011–a drop Chen Lili attributes to the prevention program, under which 12,800 cases of severe thalassemia have been diagnosed in utero. "
140. "The goal of specific medical management of infertility is to diagnose reversible causes of infertility and treat them with appropriate medications to achieve seminal improvement and pregnancy." Nonsurgical treatment of male infertility: specific and empiric therapy, Biologics 2007 September; 1(3): 259–269.
141. Annapurna Poduri et al (2013) Somatic Mutation, Genomic Variation, and Neurological Disease, Science, 5 Jul 2013. They add: neuropsychiatric and pediatric disorders are under strong negative selection because these patients are less likely to bear offspring. They point out, however, that several severe diseases can not be predicted and prevented because they are caused by somatic mutations and the fetus is a mosaic. Important review article.
142. Marcy Darnovsky (2013) A slippery slope to human germline modification, Nature 11 Jul 13. "Mitochondrial-replacement procedures would constitute germline modification." and: 'three-parent babies': it would involve a woman affected by mitochondrial disease, whose egg provides a nucleus, a second woman to provide a 'healthy' egg and a man to provide sperm. – However, the question is: would mitochondrial replacement procedures constitute germline modification at all? Because it involves natural occurring mitogenomes. Indeed, every human couple that produces a child are experimenting with a new combination of a nuclear and a mitogenome with unpredictable outcomes.
143. The Observer, 14 jul 13.
144. Steven Pinker (2011) The Better Angels of Our Nature, p. 385
145. Philippe Leboulch (2013) Gene therapy: Primed for take-off, Nature, 15 August 2013
146. Inder M. Verma (2013) Gene Therapy That Works, Science 23 August 2013
147. Klaus Reinhardt et al (2013) Mitochondrial Replacement, Evolution, and the Clinic, Science, 20 Sep 2013:
     "In conclusion, recent technical advances suggest that MR-assisted gene therapy could soon be available to help female sufferers of mitochondrial diseases have healthy children..."
148. George Church (2013) 'Improving genome understanding', Nature 10 Oct 2013. See also: Jewish Genetic Testing for Rare Disorders.
149. Bridget Wilcken (2013) Newborn Screening: Gaps in the Evidence, Science, 11 Oct 2013.
150. Theresa Morris (2013) Cut It Out: The C-Section Epidemic in America. Review in Nature (17 Oct 2013) "Birth by Caesarean section is expensive and carries a higher risk of medical complications than vaginal birth. Yet in 2011, 33% of US births were by Caesarean."
151. Helen Shen (2013) Precision gene editing paves way for transgenic monkeys. Nature online 06 November 2013
152. Eliot Marshall (2013) California Moves Shake Up Prenatal Gene Testing Market, Science 8 Nov 2013: "California agreed on 1 November to subsidize these fetal DNA tests—known as noninvasive prenatal testing—through the state's genetic diseases program, which screens about 400,000 women a year."
153. David J. Segal and Joshua F. Meckler (2013) Genome Engineering at the Dawn of the Golden Age, Annual Review of Genomics and Human Genetics, Vol. 14: 135-158 (August 2013)
154. Gerald Schwank et al (2013) Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of Cystic Fibrosis Patients, Cell Stem Cell, Volume 13, Issue 6, 5 December 2013
155. David Barker et al (2013) Developmental biology: Support mothers to secure future public health, Nature 11 Dec 2013. "Health in adulthood is associated with how people had grown in the womb. ... The Hertfordshire data and similar records from other UK towns revealed, for instance, that a person weighing 2.7 kilograms (6 pounds) at birth has a 25% higher risk of contracting heart disease in later life, and a 30% higher risk of having a stroke, compared with someone weighing 4.1 kilograms (9 pounds) at birth."
156. CRISPRs (Clustered Regularly Interspaced Palindromic Repeats) are DNA sequences that many bacteria and archaea use to defend themselves. They encode RNAs that can specifically recognize a target sequence in a viral genome. The RNAs work in complex with a CRISPR-associated protein, or Cas, which snips the DNA of the invader. A CRISPR system can be reprogrammed to edit potentially any specific DNA target. It works in eukaryotes.
157. "365 days: Nature's 10. Ten people who mattered this year. Nature 18 December 2013
158. The cost of ivacaftor is $311,000 per year according to wikipedia page Ivacaftor accessed 23 Jan 2014.
159. The five-year relative survival rates for pancreatic cancer are the lowest of the 21 most common cancers in England (Pancreatic cancer survival statistics). Pancreatic cancer has one of the highest fatality rates of all cancers, and is the fourth-highest cancer killer among both men and women worldwide (wikipedia). This means pancreatic cancer acts as negative selection.
160. Elizabeth Pennisi (2014) 'Editing of Targeted Genes Proved Possible in Monkeys', Science 31 January 2014. Other reearchres are working on animal models of a genetically inherited form of autism (SHANK3) and Parkinson's disease.
161. H. Bundy, D. Stahl, J. H. MacCabe (2011) 'A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives', Acta Psychiatrica Scandinavica, Volume 123, Issue 2, pages 98–106, February 2011
162. Emily Underwood (2014) Can Down Syndrome Be Treated? Science 28 February 2014
163. Narayana Annaluru et al (2014) Total Synthesis of a Functional Designer Eukaryotic Chromosome, Science 4 April 2014.
164. Elizabeth Pennisi (2014) Building the Ultimate Yeast Genome, Science 4 April 2014: To increase the genome's stability, they took out mobile DNA elements, such as retrotransposons, introns and other noncoding DNA. It took Codon Devices more than eleven months to deliver a 90,000-base circular chromosome.
165. Daniel G. Gibson, J. Craig Venter (2014) Synthetic biology: Construction of a yeast chromosome, Nature 8 May 2014
166. Indrani Sarkar et al (2014) HIV-1 Proviral DNA Excision Using an Evolved Recombinase, Science 29 June 2007
167. Schneider, et al (2009) 'Population-based Tay-Sachs screening among Ashkenazi Jewish young adults in the 21st Century: Hexosaminidase A enzyme assay is essential for accurate testing'. Am J Med Genet, Part A 149A:2444-2447. See also: Prevention of Tay–Sachs disease.
168. Oliver Venn et al (2014) Strong male bias drives germline mutation in chimpanzees, Science 13 June 2014
169. Tian Wang et al (2014) Polar Body Genome Transfer for Preventing the Transmission of Inherited Mitochondrial Diseases, Volume 157, Issue 7, 19 June 2014, Pages 1591–1604
170. Matthew C. Keller, Geoffrey Miller (2006) Resolving the paradox of common, harmful, heritable mental disorders: Which evolutionary genetic models work best? Behav Brain Sci. 2006
171. CRISPR corrects β-thalassaemia (Nature, 14 Aug 14): The CRISPR–Cas9 gene-editing technique is used to correct mutations in the β-globin gene in induced pluripotent stem cells of patients with β-thalassaemia.
172. Chengzu Long (2014) Prevention of muscular dystrophy in mice by CRISPR/Cas9–mediated editing of germline DNA, Science 5 September 2014
173. However: "Disorder-causing de novo mutations are hard to detect – they have to be identified among a host of other, innocuous genetic changes. ... Even the best software tools come up with 2–3 times as many false positives as true positives when analysing whole-genome sequence. ... Between 20% and 90% of the de novo mutations detected by software and with the help of whole-genome sequencing can be false positives." Vivien Marx (2014) When disease strikes from nowhere, Nature, 513, 445–448 (18 September 2014)
174. Rett syndrome: Rett syndrome is almost always seen in girls. Males who carry the abnormal MECP2 gene on their only X chromosome will usually develop a serious condition known as infantile encephalopathy, which is often fatal at a very young age. The lifespan of someone with the condition is generally shortened, often because of life-threatening arrhythmias, but many people live well into middle age and beyond.
175. Julie Gould (2014) Gene therapy: Genie in a vector, Nature, 515, 27 November 2014: "DNA with a functional factor IX gene was bundled into the molecular wrapper of a virus –known as AAV8– then shuttled into liver cells, where factor IX is normally made.". There are more than 2,000 mutations for haemophilia A.
176. Simon C. Johnson (2014) A target for pharmacological intervention in an untreatable human disease, Science 5 December 2014.
177. Frank M. J. Jacobs et al (2104) An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons, Nature, 516, 242-245 (11 December 2014)
178. David Cyranoski (2015) 'Scientists sound alarm over DNA editing of human embryos - Experts call for halt in research to work out safety and ethics issues', Nature News, 12 March 2015. ( "There are also suspicions that scientists have already created human embryos with edited genomes." )
179. Sangamo BioSciences has used zinc-finger nucleases, an older gene-editing technology, to remove a gene from white-blood cells that encodes the receptor to which HIV binds to enter the cells. Sangamo has already demonstrated the safety of its modified white-blood cells in a clinical trial of people with HIV. from: 'Ethics of embryo editing divides scientists', Nature, 19 Mar 2015.
180. According to Nobel-prizewinning geneticist Craig Mello (see: note 179).
181. Edward Lanphier et al (2015) Don’t edit the human germ line, Nature - Comment 12 March 2015 online. "Heritable human genetic modifications pose serious risks, and the therapeutic benefits are tenuous, warn Edward Lanphier, Fyodor Urnov and colleagues."
182. National Human Genome Research Institute website. (accessed 31 Mar 2015)
183. Heidi Ledford (2015) Mini enzyme moves gene editing closer to the clinic. Discovery expands potential CRISPR toolbox for treating genetic diseases in humans. Nature News and Views, 1 Apr 2015. : "biomedical engineer Charles Gersbach of Duke University in Durham, North Carolina, is eager to use the smaller Cas9 enzyme in mice to try to correct mutations associated with Duchenne muscular dystrophy, a devastating human disease that strikes 1 in 3,500 boys worldwide."
184. David Baltimore et al (2015) A prudent path forward for genomic engineering and germline gene modification. Science 3 April 2015.
185. David Cyranoski, Sara Reardon (2015) Chinese scientists genetically modify human embryos, Rumours of germline modification prove true – and look set to reignite an ethical debate. Nature News 22 April 2015
186. Infectious diseases: sleeping sickness, leishmaniasis, and Chagas disease: these are responsible for high mortality and morbidity among the world's poorest populations.
187. Michael Lynch (2015) Genetics: Feedforward loop for diversity, Nature News & Views. 23 Jul 2015
188. Gene test
189. John Travis Germline editing dominates DNA summit, Science, 11 dec 2015
190. R. Isasi, E. Kleiderman, B. M. Knoppers: Editing policy to fit the genome? Science, 22 Jan 2016.
191. Emily Underwood (2016) People on autism spectrum die 18 years younger than average, Science, Mar. 17, 2016
192. Diabetes Life Expectancy, accessed: 8 Jun 2016.
193. Promising gene therapies pose million-dollar conundrum, Nature, 16 Jun 2016
194. Jason Bittel (2016) Tardigrade protein helps human DNA withstand radiation, Nature, 20 September 2016.
195. Sam Wong (2015) Elephants almost never get cancer thanks to multiple gene copies, New Scientist, 8 October 2015
196. Caitlin Nichols (2015) The Elephant in the Room: Gene Copy Number and Cancer, Harvard University.
197. Jef D. Boeke (2016) The Genome Project–Write, Science, 2 Jun 2016. (contrasting it with the finished Human Genome Project which was essentially HGP-Read).
198. Kelly Servick (2016) Scientists reveal proposal to build human genome from scratch, Science 2 Jun 2016
199. Orkambi, a New Cystic Fibrosis Drug, Wins F.D.A. Approval, NYTIMES, July 2, 2015
200. Kelley Harris (2017) Reading the genome like a history book, Science, 08 Dec 2017
     What is 'the' mutation frequency? is not quite the right question. The particular DNA motif TCC appears to have mutated much more often within the European population than in either Africans or East Asians.
201. Ruth De Quincey (2017) Alcohol & Breast Cancer Infographic November 2, 2017
202. Susanne N. Gröbner, et al (2018) The landscape of genomic alterations across childhood cancers, Nature 15 Mar 2018.
203. Michael Lynch (2016) 'Mutation and Human Exceptionalism: Our Future Genetic Load', Genetics 2016 202(3): 869–875. (free)
     "This results in a relaxation of selection against mildly deleterious mutations, including those magnifying the mutation rate itself."
204. Live bacteria deliver crucial enzymes straight to the gut, (Nature Biotechnol. (2018)) 13 Aug 18
205. Heidi Ledford (2020) How precision medicine paved the way to the first cystic fibrosis drug, Nature, BOOK REVIEW 26 October 2020
206. Jocelyn Kaiser (2022) Enzyme treatment given directly to fetus prevents symptoms of rare genetic disease, Science 9 Nov 2022.
207. The Cost of Living with Sickle Cell Disease hematology.org May 16 2022.
208. FDA Approves First CRISPR Gene Editing Treatment for Sickle Cell Disease, Scientific American 8 Dec 2023.
209. Paula Navas also experienced the consequences of the crisis first-hand [in Venezuela]. In 2017, she lost her 22-year-old daughter Aldeny. She suffered from diabetes, but there was no insulin available in the hospitals. Her daughter fell into a coma and died. 28 Jul 2024

       Reviews  

• A review of Narrow Roads of Gene Land Volume 2.
• Ullica Segerstrale (2013) Nature's Oracle: A Life of W. D. Hamilton, Oxford University Press, USA (April 1, 2013). I guess chapter 'It is a Sick World' deals with eugenics (?). See also:
  • a review of: Nature's Oracle: The Life and Work of WD Hamilton by Ullica Segerstrale – Guardian, review, 21 Feb 2013. The most important evolutionary theorist since Darwin had an eye for patterns but a blindness for people.
    A review of Ullica Segerstrale in: Journal of the History of Biology, November 2013, Volume 46, Issue 4, pp 757-759
  • Nature (21 Mar 13) review: Evolutionary biology: Gentle giant of genetics (Oren Harman). Oren Harman assesses the first biography of biologist W. D. Hamilton, the 'greatest Darwinian since Darwin'.
  • Science (12 Apr 13): "Segerstrale captures the essence of Hamilton's science and personality remarkably well. She skillfully unravels the intricate connections between his brilliant intellect, fearless engagement, skepticism toward established authority, fondness for Neotropical wasps, and uneasiness with social situations."
• Bill Hamilton, by Andrew Brown, Prospect magazine - January 2003. This is a rare review of Hamilton's eugenic views. I only discovered it july 2012. It contains scientific errors. Andrew Brown is the author of Darwin Wars (2000).

       Further Reading  

• wikipedia: All Watched Over by Machines of Loving Grace
• wikipedia: W. D. Hamilton
• W. D. Hamilton (2003) A review of Dysgenics: Genetic Deterioration in Modern Populations, Annals of Human Genetics, Volume 64, Issue 4, pages 363–374, July 2000. abstract, pdf.
• Gert Korthof (2008) Charles Darwin on the origin of human morality and the problem of eugenics on this website.
• Review of Mendel's Demon (on this site): "Ridley states that "a life form cannot exist if it makes more than ONE mistake per offspring" (p78). So here is a paradox. We should all be dead. The human species should have been extinct for long. How we escape the paradox is the story of the book."
• J. C. Sanford (2005) Genetic Entropy & The Mystery of the Genome, Ivan Press paperback 202 pages. See: Chapter 8. "The central thesis of this book is that no form of selection can stop genomic degeneration." (p. 117). The scientist says: Science has explained many things about the universe. Your genome is degenerating. Have a nice day. (here).
• Alan D Lopez et al Global Burden of Disease and Risk Factors, 2006. If genetic diseases significantly contribute to the global burden of disease they must show up in these data! However, the report does not have a category 'genetic diseases' (see: Classification of Causes of Disease and Injury), so it is a lot of work to disentangle the genetic diseases from the rest.
• Armand Leroi (2006) The future of neo-eugenics, EMBO reports (2006) 7, 1184 - 1187. (free article). "Now that many people approve the elimination of certain genetically defective fetuses, is society closer to screening all fetuses for all known mutations?". Important article.
• Stephen F. Kingsmore, Carol J. Saunders (2011) Deep Sequencing of Patient Genomes for Disease Diagnosis: When Will It Become Routine? Science Translational Medicine 15 June 2011: Vol. 3, Issue 87, p. 87ps23
• ScienceDaily Spontaneous Mutations Important Cause of Mental Retardation (Dec. 7, 2010). Shows how genomics is changing clinical genetics.
• James F. Crow (1997) The high spontaneous mutation rate: Is it a health risk? PNAS August 5, 1997. Important article (see note 38).
• Gregory Stock (Editor), John Campbell (Editor) (2000) Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pass to Our Children. Oxford University Press.
• Gregory Stock (2002) 'Redesigning Humans: Our Inevitable Genetic Future', Houghton Mifflin Harcourt.
• Mark S. Frankel, Audrey R. Chapman (2000) 'Human Inheritable Genetic Modifications. Assessing Scientific, Ethical, Religious, and Policy Issues'. Prepared by the American Association for the Advancement of Science (AAAS). (free).
• Audrey R. Chapman and Mark S. Frankel (2004) Designing Our Descendants: The Promises and Perils of Genetic Modifications, Johns Hopkins Univ. Press, 2003. Detailed contents of the book plus summaries of chapters. PART II: Scientific Considerations. PART III: Ethical and Religious Issues. PART IV: Policy Issues. Review in: Perspectives in Biology and Medicine 47.3 (2004) 468-470 (some religious authors are against improving humans!).
• J. Robert Loftis (2005) Germ-Line Enhancement of Humans and Nonhumans, Kennedy Institute of Ethics Journal, Volume 15, Number 1, March 2005 . Conclusion: the discrepancy in attitude toward human and nonhuman germ-line enhancement is unjustified.
• Nathaniel Comfort (2012) The Science of Human Perfection: How Genes Became the Heart of American Medicine, Yale University Press. (He reviewed 'Life at the Speed of Light' for Science.) "The "Science of Human Perfection" traces the history of the promises of medical genetics and of the medical dimension of eugenics. ... He argues that medical genetics is closely related to eugenics." It looks as if Comfort wants to argue against medical genetics.
• Daniel Scherman, Ed. (2014) Advanced Textbook on Gene Transfer, Gene Therapy and Genetic Pharmacology. Principles, Delivery and Pharmacological and Biomedical Applications of Nucleotide-Based Therapies. Imperial College Press, London, 2014
• Aubrey de Grey (2008) Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime, St. Martin Griffin, paperback. de Grey's goal is treating the aging body. Although he favors in some instances gene therapy, it is always somatic gene therapy and never germline therapy or both. That implies that his anti-aging therapy has to be repeated for every individual of every generation. However, if it makes sense to study the genome of Bowhead whales (they live for over 200 years), then it also makes sense to improve the human genome, because the genome is an important cause of lifespan. 25 May 2014
• Juan Enriquez, Steve Gullans (2015) Evolving Ourselves. How Unnatural Selection and Nonrandom Mutation are Changing Life on Earth
  Evolution is now increasingly driven by two forces: Unnatural Selection (what lives and dies has to do with human desires and choices, not the natural ability to reproduce and thrive) and Nonrandom Mutation (our techniques have gotten so precise that we can drastically alter the genetics of any life form). 2 Aug 2014
• Alexey S. Kondrashov (2017) Crumbling Genome: The Impact of Deleterious Mutations on Humans.
  "A thought-provoking exploration of deleterious mutations in the human genome and their effects on human health and wellbeing". This is exactly the subject of this review. Unfortunately, the book is $80. Have a look at google books. 6 okt 2022

       Further Reading (Dutch)  

• We zijn allemaal mutanten is een bespreking van Armand Leroi (2003) Mutants. On Genetic Variety and the Human Body, en James Crow. (korthof.blogspot.nl)
• Mijlpaal in prenatale diagnostiek: compleet dna van embryo uit bloed van de moeder bepaald (korthof.blogspot.nl)
• Het leeftijd effect van de moeder op de frequentie van chromosomale afwijkingen van het embryo (korthof.blogspot.nl)
• Pre-implantatie genetische diagnostiek (PGD) versus pre-implantatie genetische screening (PGS) (korthof.blogspot.nl)