Monday, April 30, 2007

DUCHENNE'SMaternal Grandfathers/Mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population

or intrapedigree controls (29.5 +/- 1.3).

: Am J Med Genet. 1980;7(1):27-34. Links
Frequency of new mutants among boys with Duchenne muscular dystrophy.Bucher K, Ionasescu V, Hanson J.
Haldane's rule states that one-third of the cases of an X-linked recessive lethal should represent new mutations. This rule is derived under the assumptions that there is equilibrium between mutation and selection, that mutation rates in ova and sperm are equal, and that heterozygous and homozygous normal women have the same fitness. To test this rule for Duchenne muscular dystrophy (DMD), we have examined the mothers of 55 boys with DMD (16 familial and 39 isolated cases) and classified them as carriers or noncarriers on the basis of measures of ribosomal protein synthesis (RPS). Of the 55 mothers, only nine (16.4%) are classified as noncarriers, a figure significantly different from the expected one-third. When the analysis is limited to the 39 mothers of isolated cases, 23.1% (9/39) are classified as noncarriers, still significantly different than expected under Haldane's rule. Violation of any of the assumptions under which Haldane's rule is derived could lead to deviations from the expected one-third new mutants. We find the most likely explantation to be a higher male than female mutation rate. This is supported also by the finding that maternal grandfathers in whom a mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population or intrapedigree controls (29.5 +/- 1.3).
PMID: 7211951 [PubMed - indexed for MEDLINE]

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Thursday, April 26, 2007

Increased Paternal Age Found in Neurofibromatosis in 1973

1: Humangenetik. 1975 Jun 19;28(2):129-38. Links
On the mutation rate of neurofibromatosis.Sergeyev AS.
A genetic study of 124 cases of neurofibromatosis was performed. The contingent of probands was mainly represented by a Russian population, most of the individuals being born in the European part of the RSFSR. Both parents of the probands were examined in only 58 cases, the proportion of sporadic cases in this group being 0.79, as compared to 0.77 for the whole group under study. The existing data evaluated by a direct method are not yet sufficient for a decisive estimation of the penetrance, which, however, cannot be under 80%. Segregation analysis of descendants from particular marriages showed a good correspondance to the hypothesis of Mendelian dominance (32 affected children out of 65). These results analyzed together with those obtained by other authors permit an inference on the full penetrance of neurofibromatosis. The genetic interpretation of sporadic cases as a result of new mutations is presented. The prevalence of neurofibromatosis among the 16-year-old youths was evaluated as 12.8 with 10-(5). This value is suggested to be an estimation of the incidence of the condition in the general population, the mutation rate evaluated by a direct method being equal to 4.4 with 10-(5) divided by 4.9 with 10-minus 5. The increased birth order of probands in sporadic cases (against the theoretical expectation) as well as increased paternal age (as compared with controls) were found to be statistically significant (P equals 0.004 and P equals 0.03, respectively) while the difference in maternal ages was statistically insignificant (P equals 0.008). No statistical relationship between sporadic cases and occupational exposure of parents to deleterious chemical and physical factors was found.

PMID: 125227 [PubMed - indexed for MEDLINE]


Mean Paternal Age Was 32.8 in von Recklinghausen disease

1: Am J Med Genet. 1984 May;18(1):169-76. Links
The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations.Riccardi VM, Dobson CE 2nd, Chakraborty R, Bontke C.
Von Recklinghausen neurofibromatosis is characterized by a relatively large proportion of apparently nonfamilial cases, presumed spontaneous mutations. This paper analyzes the distribution of paternal and maternal ages for 187 patients with von Recklinghausen disease representing the first definite case in their respective families. Mean paternal age was 32.8 years and mean maternal age was 27.4 years, both being significantly greater than for control populations (P equal to or less than .001). The advanced paternal age was not accounted for by the increase in maternal age. The methodology of controlling the general population paternal ages for each patient's birth year is described.

PMID: 6430086 [PubMed - indexed for MEDLINE]


Neurofibromatosis 2 50% de novo mutations Paternal Age ??

Disease characteristics. Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected persons develop bilateral vestibular schwannomas by the age of 30 years. Affected indivduals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, and rarely, ependymomas and astrocytomas. Posterior subcapsular lens opacities that rarely progress to a visually significant cataract are the most common ocular findings. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy, a squint (third nerve palsy), or hand/foot drop.

Diagnosis/testing. Diagnosis of NF2 is based on clinical criteria. NF2f is the only gene known to be associated with neurofibromatosis type 2. Confirmatory molecular genetic testing of the NF2 gene is clinically available. The main role of molecular genetic testing is in early detection of at-risk individuals (primarily the children of classically affected individuals) for the purpose of medical management and surveillance. Prenatal diagnosis is clinically available.

Management. Treatment of vestibular schwannoma is primarily surgical. Stereotactic radiosurgery, most commonly with the gamma knife, may be an alternative to surgery. Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. Radiation therapy of NF2-associated tumors should be carefully considered since radiation exposure, especially in childhood, may induce, accelerate, or transform tumors. Treatment for hearing loss includes referral to an audiologist, lip-reading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants. Individuals with visual impairment require routine, complete eye examinations. Surveillance for affected or at-risk individuals includes annual MRI beginning around age ten to 12 years and continuing until at least the fourth decade of life. Hearing evaluation including BAER testing may also be useful.

Genetic counseling. NF2 is inherited in an autosomal dominant manner. About 50% of individuals with NF2 have an affected parent and 50% have NF2 as the result of a de novo gene mutation. However, 25-30% of those representing simplex cases (i.e., individuals with no family history of NF2) are mosaic for an NF2 mutation. The risk to the sibs of the proband depends upon the genetic status of the parents. If a parent of the proband is affected, the risk to the sibs is 50%. Prenatal testing is clinically available. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

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Tuesday, April 24, 2007


The drug, known as PTC124, has already had encouraging results in patients with Duchenne muscular dystrophy and cystic fibrosis. The final phase of clinical trials is to begin this year, and it could be licensed as early as 2009.

As well as offering hope of a first effective treatment for two conditions that are at present incurable, the drug has excited scientists because research suggests it should also work against more than 1,800 other genetic illnesses.

PTC124 targets a particular type of mutation that can cause very different symptoms according to the gene that is disrupted. This makes it potentially useful against a range of inherited disorders.

Related Links
‘My little boy is going to die, but new drug offers hope for others’
Screening for cystic fibrosis saves money
Designer baby to beat risk of Alzheimer’s
The same drug could be given to patients with Duchenne muscular dystrophy, the most serious form of the muscle-wasting condition, cystic fibrosis, which mainly affects the lungs, and haemophilia, in which the blood does not clot. It can be taken orally, and safety trials have not revealed any major side effects.

“There are literally thousands of genetic diseases that could benefit from this approach,” Lee Sweeney, of the University of Pennsylvania, who is leading the research, said. “What’s unique about this drug is it doesn’t just target one mutation that causes disease, but a whole class of mutations.”

In most genetic conditions, between 5-15 per cent of cases are caused by a defect called a “nonsense mutation”. Genes are instruction manuals for cells to make proteins, but nonsense mutations in effect introduce a command halfway through that stops production. The kind of protein disrupted determines the nature of the disease.

In Duchenne muscular dystrophy, for example, the protein necessary for normal muscle development is not made, and the fatal wasting disease is the result. In haemophilia, it is the gene for the clotting agents factor VIII or factor IX that is disrupted.

PTC124 works by binding to a part of the cell called the ribosome, which translates genetic code into protein, and allows it to ignore nonsense mutations. The gene can be read straight through and a normal protein is produced.

The beauty of the drug is that it should be useful with

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Thursday, April 12, 2007



1: Am J Med Genet. 1997 Nov 12;72(4):394-8. Related Articles, Links

Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome.

Tolarova MM, Harris JA, Ordway DE, Vargervik K.

Department of Growth and Development, School of Dentistry, University of California, San Francisco, 94143-0442, USA.

Apert syndrome was studied to determine birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity among 2,493,331 live births registered in the California Birth Defects Monitoring Program (CBDMP) from 1983 through 1993; 31 affected infants were identified. The sample was completed with an additional 22 cases from the Center for Craniofacial Anomalies (CCA), University of California, San Francisco, for a total of 53 affected children. Birth prevalence, calculated from the CBDMP subsample, was 12.4 cases per million live births (confidence interval [CI] 8.6,17.9). The calculated mutation rate was 6.2 x 10(-6) per gene per generation. Asians had the highest prevalence (22.3 per million live births; CI 7.1,61.3) and Hispanics the lowest (7.6 per million, CI 3.3-16.4). In the large population-based CBDMP subsample, there was an almost equal number of affected males and females, (sex ratio 0.94) but in the clinical CCA subsample, there were more affected females (sex ratio 0.79). For all cases, the mean age of mothers was 28.9+/-6.0 years, and of fathers was 34.1+/-6.2 years. Almost half of fathers were older than 35 years when the child was born; for more than 20% of cases, both parents were older than 35 years. These findings may support the view that point mutations appear to be more commonly associated with paternal than with maternal alleles. Representing the largest systematically ascertained population-based study of Apert syndrome to date, they provide a reliable basis for genetic counseling and decision-making, and for focused research to define the cause of this syndrome.

PMID: 9375719 [PubMed - indexed for MEDLINE]


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Saturday, April 7, 2007

Sporadic Neurofibromatosis and Advanced Paternal Age

1: J Child Neurol. 1993 Oct;8(4):395-402. Links
Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic.North K.
Department of Neurology, Children's Hospital, Camperdown, Sydney, Australia.

Neurofibromatosis type 1 is a common multisystem disorder, best managed in a multidisciplinary clinic. In 1991, the first Australian neurofibromatosis clinic was established at the Children's Hospital, Camperdown, and the clinical characteristics of the first 150 families are reviewed. Two hundred individuals were assessed; there was an equal sex distribution, and 55% of cases were sporadic. Advanced paternal age appeared to predispose to new mutations in the neurofibromatosis gene. Cafe-au-lait spots and axillary freckling were important to the diagnosis of neurofibromatosis type 1 during childhood, and neurofibromas and Lisch nodules, although often not appearing until after puberty, were present in almost all patients over 30 years of age. Short stature (27%), macrocephaly (43%), scoliosis (20.5%), and learning disabilities (45%) were common associated features. The prevalence of disease complications was similar to the major US and European studies.

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Wednesday, April 4, 2007

Spontaneous Beta-Thalassemia and Advanced Paternal Age

: Blood. 1989 Aug 1;74(2):852-4. Links
Characterization of a spontaneous mutation in beta-thalassemia associated with
advanced paternal age.Chehab FF, Winterhalter KH, Kan YW.
Howard Hughes Medical Institute, University of California, San Francisco 94143.

We characterized the molecular defect in a Swiss patient with a spontaneous beta-thalassemia mutation. Cloning and DNA sequencing of her beta-globin gene revealed a new frameshift mutation due to a single nucleotide deletion at codon 64 of the beta-globin gene. Restriction site polymorphism showed that the mutation arose on her paternal chromosome. Direct sequencing of a polymerase chain reaction amplified DNA segment showed absence of the lesion in both alleles of her father's beta-globin gene and confirmed the spontaneous nature of this mutation.

PMID: 2665856 [PubMed - indexed for MEDLINE]


Neurofibromatosis(vonRecklinghausen's disease, NF1) paternal age effect

: Hum Genet. 1992 May;89(3):281-6. Links
Genetics of neurofibromatosis 1 in Japan: mutation rate and paternal age effect.Takano T, Kawashima T, Yamanouchi Y, Kitayama K, Baba T, Ueno K, Hamaguchi H.
Department of Hygiene, Teikyo University School of Medicine, Tokyo, Japan.

We have performed formal genetic studies on 26 patients (14 males, 12 females) with neurofibromatosis 1 (von Recklinghausen's disease, NF1) in Japan. Family studies of 74 members of 18 kindreds revealed that 50% of the cases were caused by a new mutation; the mutation rate was assumed to be 7.3-10.5 x 10(-5). A tendency of paternal age effect, which was not accounted for by the maternal age effect, was observed, but live-birth order had no significant effect. Genetic linkage of neurofibromatosis 1 to the NF1 gene or the genetic marker in the pericentric region of chromosome 17 was established in 3 informative families.

PMID: 1351032 [PubMed - indexed for MEDLINE]

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Athetoid/dystonic cerebral or hemiplegic cerebral palsy and Paternal Age

: J Med Genet. 1993 Jan;30(1):44-6. Links
Parental age, genetic mutation, and cerebral palsy.Fletcher NA, Foley J.
Department of Neurological Sciences, St Bartholomew's Hospital, London.

Parental age and birth order were studied in 251 patients with cerebral palsy. No parental age or birth order effects were observed in spastic quadriplegia or diplegia, but a paternal age effect was detected in those with athetoid/dystonic cerebral palsy and congenital hemiplegia. These observations indicate that some cases of athetoid/dystonic or hemiplegic cerebral palsy might arise by fresh dominant genetic mutation.

PMID: 8423607 [PubMed - indexed for MEDLINE]

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The Age of the Father is the Main Factor Determining the Human Spontaneous Mutation Rate

1: Environ Mol Mutagen. 1993;21(2):122-9. Links
Erratum in:
Environ Mol Mutagen 1993;21(4):389.
How much do we know about spontaneous human mutation rates?Crow JF.
Genetics Department, University of Wisconsin, Madison 53706.

The much larger number of cell divisions between zygote and sperm than between zygote and egg, the increased age of fathers of children with new dominant mutations, and the greater evolution rate of pseudogenes of the Y chromosome than of those on autosomes all point to a much higher mutation rate in human males than in females, as first pointed out by Haldane [Ann Eugen 13:262-271, 1947] in his classical study of X-linked hemophilia. The age of the father is the main factor determining the human spontaneous mutation rate, and probably the total mutation rate. The total mutation rate in Drosophila males of genes causing minor reduction in viability is at least 0.4 per sperm, and may be considerably higher. The great mutation load implied by a rate of approximately 1 per zygote can be greatly ameliorated by quasi-truncation selection. Corresponding data are not available for the human population. The evolution rate of pseudogenes in primates suggests some 10(2) new mutations per zygote. Presumably the overwhelming majority of these are neutral, but even the approximate fraction is not known. Statistical evidence in Drosophila shows that mutations with minor effects cause about the same heterozygous impairment of fitness as those that are lethal when homozygous. The magnitude of heterozygous effect is such that almost all mutant genes are eliminated as heterozygotes before ever becoming homozygous. Although quantitative data in the human species are lacking, anecdotal information supports the conclusion that partial dominance is the rule here as well. This suggests that if the human mutation rate were increased or decreased, the effects would be spread over a period of 50-100 generations.

PMID: 8444142 [PubMed - indexed for MEDLINE]

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New Mutations For Huntington's Disease From Advanced Paternal Age

: Nat Genet. 1993 Oct;5(2):174-9. Links
Comment in:
Nat Genet. 1993 Nov;5(3):215.
Molecular analysis of new mutations for Huntington's
disease: intermediate alleles and sex of origin effects.Goldberg YP, Kremer B, Andrew SE, Theilmann J, Graham RK, Squitieri F, Telenius H, Adam S, Sajoo A, Starr E, et al.
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

Huntington's disease (HD) is associated with expansion of a CAG repeat in a novel gene. We have assessed 21 sporadic cases of HD to investigate sequential events underlying HD. We show the existence of an intermediate allele (IA) in parental alleles of 30-38 CAG repeats in the HD gene which is greater than usually seen in the general population but below the range seen in patients with HD. These IAs are meiotically unstable and in the sporadic cases, expand to the full mutation associated with the phenotype of HD. This expansion has been shown to occur only during transmission through the male germline and is associated with advanced paternal age. These findings suggest that new mutations for HD are more frequent than prior estimates and indicate a previously unrecognized risk of inheriting HD to siblings of sporadic cases of HD and their children.

PMID: 8252043 [PubMed - indexed for MEDLINE]


Nature Genetics 5, 174 - 179 (1993)
Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects
Y. Paul Goldberg1, Berry Kremer1, Susan E. Andrew1, Jane Theilmann1, Rona K. Graham1, Ferdinando Squitieri1, Håkan Telenius1, Shelin Adam1, Anaar Sajoo1, Elizabeth Starr1, Arvid Heiberg2, Gerhard Wolff3 & Michael R. Hayden1
1Department of Medical Genetics, University of British Columbia, 416−2125 East Mall Vancouver, British Columbia V6T 2C1, Canada

2Frambu Helsesenter, 1404 Siggerud, Norway

3Institut für Humangenetik und Anthropologie, Universität Freiburg, Breisacherstrasse 33, D-7800 Freiburg, Germany

Correspondence should be addressed to M.R.H.

Harper, P.S. Huntington's Disease (W.B. Saunders, London, 1991).
Hayden, M.R. Huntington's Chorea (Springer-Vertag, New York, 1981).
Vogel, F. & Motulsky, A. Human Genetics 2nd edn (Springer-Verlag, New York, 1986).
Huntington Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on HD chromosomes. Cell 72, 971−983 (1983).
Andrew, S.E. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington Disease. Nature Genet. 4, 398−403, (1993).
Wolff, G. et al. New Mutation to Huntington's Disease. J. med. Genet. 26, 18−27 (1989).
Barattser, M., Bum, J. & Fazzone, T.A. Huntington's chorea arising as a fresh mutation. J. med. Genet. 20, 459−460 (1983).
Shaw, M. & Caro, A. The mutation rate to Huntington's chorea. J. Med. Genet. 19, 161−167 (1982).
Chiu, E. & Brackenridge, C.J. A probable case of mutation in Huntington's disease. J. med. Genet. 13, 75−77 (1976).
Stevens, D. & Parsonage, M. Mutation in Huntington's chorea. J. Neurol. Neurosurg. Psychiat. 32, 140−143 (1969).
MacDonald, M.E. et al. The Huntington's disease candidate region exhibits many different haplotypes. Nature Genet. 1, 99−103 (1969).
Andrew, S.E. et al. DNA analysis of distinct populations suggest multiple origins for the mutation causing Huntington Disease. Clin. Genet. 43, 286−294 (1993).
Fu, Y-h. et al. Variation of the CCG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047−1058 (1991).
Kremer, E.J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711−1714 (1991).
Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science 255, 1253−1255 (1992).
Fu, Y-H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256−1258 (1992).
Brook, J.D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 68, 799−808 (1992).
Barcelo, J.M. et al. Intergenerational stability of the myotonic dystrophy protomutation. Hum. molec. Genet 6, 705−709,1993.
Brook, J.D. Retreat of the triplet repeat? Nature Genet. 3, 279−281 (1993).
Penrose, L.S. Parental age and mutation. Lancet II, 312 (1955).
Penrose, L.S. Parental age in achondroplasia and mongolism. Am. J. hum. Genet. 9, 167−169 (1957).
Murdoch, J., Walker, B.A. & McKusick, V.A. Parental age effects on the occurrence of new mutations for the Marfan syndrome. Ann. hum. Genet. 35, 331−336 (1972).
Vogel, F. A probable sex difference in some mutation rates.Am. J. hum. Genet. 29, 312−319 (1977).
Kunkel, L.M. et al. Analysis of human Y chromosome specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A. 74, 1245−1249 (1977).
Goldberg, Y.P., Andrew, S.E., Clarke, L.A. & Hayden, M.R. A PCR method for accurate assessment of trinucleotide repeat expansion in Huntington Disease. Hum. molec. Genet 2, 635−636 (1993).
Zar, J.H. (ed.) Biostatistical Analysis 2nd edn 370−371 (Prentice-Hall, New Jersey, (1984).

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Costello Syndrome and Mean Paternal Age of 38 years

Am J Med Genet. 1994 Sep 1;52(3):358-9. Links
Genetics of the Costello syndrome.Lurie IW.

Department of Pediatrics, School of Medicine, University of Maryland, Baltimore.

Although Costello syndrome is considered to be an autosomal recessive disorder, review of 20 families demonstrated that the 37 sibs of the probands were all normal. In 6 families on whom pedigrees were not available, 2 affected sib-pairs were born. Even if there were no normal offspring in these latter families, the occurrence of the Costello syndrome in only 2 of 39 sibs virtually excludes an autosomal recessive inheritance pattern (P = 0.999). Moreover, a significant increase of mean paternal age (38.0 yr) and paternal-maternal age difference (7.36 yr) suggests sporadic autosomal dominant mutations as a likely cause. The 2 reported cases of affected sibs born to healthy parents may be explained by gonadal mosaicism, although heterogeneity with a small proportion of recessively inherited cases cannot be excluded.

PMID: 7528974 [PubMed - indexed for MEDLINE]

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Daughters Of Fathers 50-59 Lose about 4.4 years .......

Mutat Res. 1997 Jun 9;377(1):61-2. Links
Mutation load and human longevity.Gavrilov LA, Gavrilova NS, Kroutko VN
, Evdokushkina GN, Semyonova VG, Gavrilova AL, Lapshin EV, Evdokushkina NN, Kushnareva YE.
Center for Longevity Research at A.N. Belozersky Institute, Moscow State University, Russia.

Since paternal age at reproduction is considered to be the main factor determining human spontaneous mutation rate (Crow, J. (1993) Environ. Mol. Mutagenesis, 21, 122-129), the effect of paternal age on human longevity was studied on 8,518 adult persons (at age 30 and above) from European aristocratic families with well-known genealogy. The daughters born to old fathers (50-59 years) lose about 4.4 years of their life compared to daughters of young fathers (20-29 years) and these losses are highly statistically significant, while sons are not significantly affected. Since only daughters inherit the paternal X chromosome, this sex-specific decrease in daughters' longevity might indicate that human longevity genes (crucial, house-keeping genes) sensitive to mutational load might be located in this chromosome.

PMID: 9219579 [PubMed - indexed for MEDLINE]

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The high spontaneous mutation rate: Is it a health risk?*

James F. Crow

Proc. Natl. Acad. Sci. USA
Vol. 94, pp. 8380-8386, August 1997

Genetics Laboratory, University of Wisconsin, Madison, WI 53706

My topic is mutation. Mutation is the ultimate source of variability on which natural selection acts; for neutral changes it is the driving force. Without mutation, evolution would be impossible. My concern, however, is not with mutation as a cause of evolution, but rather as a factor in current and future human welfare. Since most mutations, if they have any effect at all, are harmful, the overall impact of the mutation process must be deleterious. And it is this deleterious effect that I want to discuss.

The ideas that I am presenting are not new. Some go back to early in the century, but the evidence has been strengthened in recent times. In this review, I shall draw on the work of many who have contributed to this history.

This lecture is dedicated to three heroes. The first is Wilhelm Weinberg, a busy German physician and obstetrician42 years of practice and more than 3,500 birthswho somehow found time to invent all manner of clever tricks for studying heredity in that recalcitrant species, Homo sapiens. He was the first to suggest that the mutation rate might be a function of paternal age (1). The second hero is J. B. S. Haldane, an eccentric polymath with an enormous number and an incredible diversity of accomplishments. He was one of the first to measure a human mutation rate and was the first to notice a sex difference in the rate (2). The third is H. J. Muller, who made mutation an experimental subject by devising an objective way of measuring it and showing that ionizing radiation is mutagenic. In the later years of his life, Muller spent much of his energy, physical and emotional, in a crusade against unnecessary human exposure to radiation. Interestingly, he gave little attention to what is surely much more important, chemical mutagens. The main reason is that when he was still active there were no known mutagens that were not highly toxic; mustard gas is an example. Had he known of relatively harmless compounds that are highly mutagenic, he would surely have extended his crusade to environmental chemicals. Curiously, although Muller emphasized the high rate of spontaneous mutation, he did not include it in his crusade, mainly, I think, because he saw no feasible way to reduce it (3).

The Nature of Mutations

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Older Paternal Age and progeria, basal cell nevus syndrome etc. 1975

1: J Pediatr. 1975 Jan;. Links
Older paternal age and fresh gene mutation86(1):84-8: data on additional disorders.Jones KL, Smith DW, Harvey MA, Hall BD, Quan L.

Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown

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