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PubMed2002

Fixation of deleterious alleles, evolution and human aging.

Human aging, like everything else in biology, only makes sense in the context of evolution. There is substantial agreement among evolutionary geneticists regarding the evolutionary underpinnings of one of the main questions of human aging i.e. 'Why do we age?', which involves the higher rate of fixation of alleles that cause deleterious post-reproductive phenotypes vs. alleles that cause deleterious pre-reproductive phenotypes. Even higher rates of fixation of deleterious mutations are predicted to occur on population genetic grounds in two non-recombinant genomes in humans i.e. the Y chromosome, and the mitochondrial genome. The added burden of deleterious mutations on the Y may explain the reduced average lifespan of males vs. females. A high predicted fixation rate of the mitochondrial genome may explain its fast rate of evolution, and the high frequency of mitochondrial disease in relationship to this genomes' small size, and may underlie the transfer of mitochondrial genes over evolutionary time to the nucleus. Thus a molecular evolutionary model of aging which focuses on increased fixation rates of (1) nuclear alleles which only have deleterious effects post-reproduction, (2) deleterious genes on the Y chromosome, and (3) deleterious genes on the mitochondrial genome, makes multiple testable predictions about the causes and mechanisms of aging.

Aging↗

PubMed1999

Evolution by small steps and rugged landscapes in the RNA virus phi6.

Fisher's geometric model of adaptive evolution argues that adaptive evolution should generally result from the substitution of many mutations of small effect because advantageous mutations of small effect should be more common than those of large effect. However, evidence for both evolution by small steps and for Fisher's model has been mixed. Here we report supporting results from a new experimental test of the model. We subjected the bacteriophage phi6 to intensified genetic drift in small populations and caused viral fitness to decline through the accumulation of a deleterious mutation. We then propagated the mutated virus at a range of larger population sizes and allowed fitness to recover by natural selection. Although fitness declined in one large step, it was usually recovered in smaller steps. More importantly, step size during recovery was smaller with decreasing size of the recovery population. These results confirm Fisher's main prediction that advantageous mutations of small effect should be more common. We also show that the advantageous mutations of small effect are compensatory mutations whose advantage is conditional (epistatic) on the presence of the deleterious mutation, in which case the adaptive landscape of phi6 is likely to be very rugged.

Bacteriophage phi 6↗

PubMed2004

Family cancer histories predictive of a high risk of hereditary non-polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1.

Hereditary non-polyposis colorectal cancer (HNPCC) results from inactivating germline mutations in a set of DNA-mismatch-repair genes, of which the most clinically relevant are hMSH2 and hMLH1. Computer-assisted pedigree risk assessment tools are available to assist in the calculation of an individual's likelihood of bearing such a deleterious mutation. One such tool, cancergene version 3.4 (http://www3.utsouthwestern.edu/cancergene) was used to assess the risk of a deleterious mutation in the genes hMSH2 and/or hMLH1 in a series of probands selected from a panel of 67 South-western Ontario kindred previously identified as likely candidates for HNPCC by established clinical criteria. A DNA sample isolated from peripheral blood leukocytes obtained from each of these probands was examined for genomic rearrangement using the multiplex ligation-dependent probe amplification (MLPA) method. Of the individuals calculated to have a risk of >50% of a hMSH2 or hMLH1 gene mutation by the CancerGene risk assessment tool, 69% (9/13) were shown to have a genomic rearrangement resulting in the deletion of one or more exons of one of these two genes. Family cancer histories predictive of a high risk of HNPCC significantly associate with a genomic rearrangement in hMSH2 or hMLH1.

Adaptor Proteins, Signal Transducing↗

PubMed1991

Transition from haploidy to diploidy.

As a direct consequence of sex, organisms undergo a haploid and a diploid stage during their life cycle. Although the relative duration of haploid and diploid phases varies greatly among taxa, the diploid phase is more conspicuous in all higher organisms. Therefore it is widely believed that diploidy offers more evolutionary possibilities and is thus nearly always selected for. We have now performed computer simulations to investigate one possible advantage of diploidy, that is, protection against the expression of deleterious mutations. Instead of comparing isolated haploid and diploid populations, we considered interbreeding haploids and diploids. Diploids invaded the population only when the dominance degree of a single deleterious mutation was smaller than about 1/2, and the condition allowing diploidy to invade depended on how harmful the mutation was.

Alleles↗

PubMed2018

Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations.

BACKGROUND: The presence of deleterious mutations in breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2) significantly increases the risk of developing some cancers, such as breast and high-grade serous cancer (HGSC) of ovarian, tubal and peritoneal origin. Risk-reducing salpingo-oophorectomy (RRSO) is usually recommended to BRCA1 or BRCA2 carriers after completion of childbearing. Despite prior systematic reviews and meta-analyses on the role of RRSO in reducing the mortality and incidence of breast, HGSC and other cancers, RRSO is still an area of debate and it is unclear whether RRSO differs in effectiveness by type of mutation carried. OBJECTIVES: To assess the benefits and harms of RRSO in women with BRCA1 or BRCA2 mutations. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 7) in The Cochrane Library, MEDLINE Ovid, Embase Ovid and trial registries, with no language restrictions up to July 2017. We handsearched abstracts of scientific meetings and other relevant publications. SELECTION CRITERIA: We included non-randomised trials (NRS), prospective and retrospective cohort studies, and case series that used statistical adjustment for baseline case mix using multivariable analyses comparing RRSO versus no RRSO in women without a previous or coexisting breast, ovarian or fallopian tube malignancy, in women with or without hysterectomy, and in women with a risk-reducing mastectomy (RRM) before, with or after RRSO. DATA COLLECTION AND ANALYSIS: We extracted data and performed meta-analyses of hazard ratios (HR) for time-to-event variables and risk ratios (RR) for dichotomous outcomes, with 95% confidence intervals (CI). To assess bias in the studies, we used the ROBINS-I 'Risk of bias' assessment tool. We quantified inconsistency between studies by estimating the I2 statistic. We used random-effects models to calculate pooled effect estimates. MAIN RESULTS: We included 10 cohort studies, comprising 8087 participants (2936 (36%) surgical participants and 5151 (64%) control participants who were BRCA1 or BRCA2 mutation carriers. All the studies compared RRSO with or without RRM versus no RRSO (surveillance). The certainty of evidence by GRADE assessment was very low due to serious risk of bias. Nine studies, including 7927 women, were included in the meta-analyses. The median follow-up period ranged from 0.5 to 27.4 years. MAIN OUTCOMES: overall survival was longer with RRSO compared with no RRSO (HR 0.32, 95% CI 0.19 to 0.54; P < 0.001; 3 studies, 2548 women; very low-certainty evidence). HGSC cancer mortality (HR 0.06, 95% CI 0.02 to 0.17; I² = 69%; P < 0.0001; 3 studies, 2534 women; very low-certainty evidence) and breast cancer mortality (HR 0.58, 95% CI 0.39 to 0.88; I² = 65%; P = 0.009; 7 studies, 7198 women; very low-certainty evidence) were lower with RRSO compared with no RRSO. None of the studies reported bone fracture incidence. There was a difference in favour of RRSO compared with no RRSO in terms of ovarian cancer risk perception quality of life (MD 15.40, 95% CI 8.76 to 22.04; P < 0.00001; 1 study; very low-certainty evidence). None of the studies reported adverse events.Subgroup analyses for main outcomes: meta-analysis showed an increase in overall survival among women who had RRSO versus women without RRSO who were BRCA1 mutation carriers (HR 0.30, 95% CI 0.17 to 0.52; P < 0001; I² = 23%; 3 studies; very low-certainty evidence) and BRCA2 mutation carriers (HR 0.44, 95% CI 0.23 to 0.85; P = 0.01; I² = 0%; 2 studies; very low-certainty evidence). The meta-analysis showed a decrease in HGSC cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.10, 95% CI 0.02 to 0.41; I² = 54%; P = 0.001; 2 studies; very low-certainty evidence), but uncertain for BRCA2 mutation carriers due to low frequency of HGSC cancer deaths in BRCA2 mutation carriers. There was a decrease in breast cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.45, 95% CI 0.30 to 0.67; I² = 0%; P < 0.0001; 4 studies; very low-certainty evidence), but not for BRCA2 mutation carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; 3 studies; very low-certainty evidence). One study showed a difference in favour of RRSO versus no RRSO in improving quality of life for ovarian cancer risk perception in women who were BRCA1 mutation carriers (MD 10.70, 95% CI 2.45 to 18.95; P = 0.01; 98 women; very low-certainty evidence) and BRCA2 mutation carriers (MD 13.00, 95% CI 3.59 to 22.41; P = 0.007; very low-certainty evidence). Data from one study showed a difference in favour of RRSO and RRM versus no RRSO in increasing overall survival (HR 0.14, 95% CI 0.02 to 0.98; P = 0.0001; I² = 0%; low-certainty evidence), but no difference for breast cancer mortality (HR 0.78, 95% CI 0.51 to 1.19; P = 0.25; very low-certainty evidence). The risk estimates for breast cancer mortality according to age at RRSO (50 years of age or less versus more than 50 years) was not protective and did not differ for BRCA1 (HR 0.85, 95% CI 0.64 to 1.11; I² = 16%; P = 0.23; very low-certainty evidence) and BRCA2 carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is very low-certainty evidence that RRSO may increase overall survival and lower HGSC and breast cancer mortality for BRCA1 and BRCA2 carriers. Very low-certainty evidence suggests that RRSO reduces the risk of death from HGSC and breast cancer in women with BRCA1 mutations. Evidence for the effect of RRSO on HGSC and breast cancer in BRCA2 carriers was very uncertain due to low numbers. These results should be interpreted with caution due to questionable study designs, risk of bias profiles, and very low-certainty evidence. We cannot draw any conclusions regarding bone fracture incidence, quality of life, or severe adverse events for RRSO, or for effects of RRSO based on type and age at risk-reducing surgery. Further research on these outcomes is warranted to explore differential effects for BRCA1 or BRCA2 mutations.

Adult↗

PubMed2006

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.

BACKGROUND & AIMS: Inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. METHODS: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. RESULTS: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. CONCLUSIONS: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia.

Lee S-C, Guo J-Y, Lim R, Soo R, Koay E, Salto-Tellez M, Leong A, Goh B-C. Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. Hereditary non-polyposis colorectal cancer (HNPCC), predominantly due to germline MLH1/MSH2 mutations, is the commonest form of hereditary colorectal cancer (CRC), but data in Asians are sparse. We sequenced the MLH1/MSH2 coding and promoter core regions in CRC patients diagnosed below age 40, and/or with multiple primary cancers or familial cancer clustering suggestive of HNPCC, and correlated deleterious mutations with clinical and tumour features. Forty-six Chinese, Malay and Indian kindreds participated. Of the 153 cancers reported in the 46 kindreds, stomach (14%) and urogenital cancers (13%) were the most common extracolonic cancers, whereas endometrial cancer comprised only 7%. Eleven different MLH1 and 12 MSH2 mutations were identified, including nine novel and four recurring mutations in the Chinese. One Indian was a compound heterozygote for an MLH1 and MSH2 mutation. The MLH1/MSH2 mutation data in the Malays and the Indians represents the first in these ethnic groups. Factors strongly associated with deleterious mutations were the Amsterdam criteria, family history of stomach or multiple primary cancers, and MSI-high tumours, whereas family history of endometrial cancer and young cancer age alone correlated poorly. Distinct clinical and molecular characteristics were identified among Asian HNPCC kindreds and may have important clinical implications.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Mutation accumulation in space and the maintenance of sexual reproduction.

The maintenance of sexual reproduction remains one of the major puzzles of evolutionary biology, since, all else being equal, an asexual mutant should have a twofold fitness advantage over the sexual wildtype. Most theories suggest that sex helps either to purge deleterious mutations, or to adapt to changing environments. Both mechanisms have their limitations if they act in isolation because they require either high genomic mutation rates or very virulent pathogens, and it is therefore often thought that they must act together to maintain sex. Typically, however, these theories have in common that they are not based on spatial processes. Here, we show that local dispersal and local competition can explain the maintenance of sexual reproduction as a means of purging deleterious mutations. Using a spatially explicit individual-based model, we find that even with reasonably low genomic mutation rates and large total population sizes, asexual clones cannot invade a sexual population. Our results demonstrate how spatial processes affect mutation accumulation such that it can fully erode the twofold benefit of asexuality faster than an asexual clone can take over a sexual population. Thus, the cost of sex is generally overestimated in models that ignore the effects of space on mutation accumulation.

Adaptation, Physiological↗

PubMed2001

Masking and purging mutations following EMS treatment in haploid, diploid and tetraploid yeast (Saccharomyces cerevisiae).

The yeast, Saccharomyces cerevisiae, was used as a model to investigate theories of ploidy evolution. Mutagenesis experiments using the alkylating agent EMS (ethane methyl sulphonate) were conducted to assess the relative importance that masking of deleterious mutations has on response to and recovery from DNA damage. In particular, we tested whether cells with higher ploidy levels have relatively higher fitnesses after mutagenesis, whether the advantages of masking are more pronounced in tetraploids than in diploids, and whether purging of mutations allows more rapid recovery of haploid cells than cells with higher ploidy levels. Separate experiments were performed on asexually propagating stationary phase cells using (1) prototrophic haploid (MAT alpha) and diploid (MATa/alpha) strains and (2) isogenic haploid, diploid and tetraploid strains lacking a functional mating type locus. In both sets of experiments, haploids showed a more pronounced decrease in apparent growth rate than diploids, but both haploids and diploids appeared to recover very rapidly. Tetraploids did not show increased benefits of masking compared with diploids but volume measurements and FACScan analyses on the auxotrophic strains indicated that all treated tetraploid strains decreased in ploidy level and that some of the treated haploid lines increased in ploidy level. Results from these experiments confirm that while masking deleterious mutations provides an immediate advantage to higher ploidy levels in the presence of mutagens, selection is extremely efficient at removing induced mutations, leading growth rates to increase rapidly over time at all ploidy levels. Furthermore, ploidy level is itself a mutable trait in the presence of EMS, with both haploids and tetraploids often evolving towards diploidy (the ancestral state of S. cerevisiae) during the course of the experiment.

Cell Division↗

PubMed1997

No mitochondrial cytochrome oxidase (COX) gene mutations in 18 cases of COX deficiency.

Cytochrome c oxidase (COX) deficiency causes a variety of neuromuscular and non-neuromuscular disorders in childhood and adulthood and can theoretically undergo either a nuclear or a mitochondrial (mt) mode of inheritance, making genetic counseling in COX deficiency particularly hazardous. In an attempt to determine the respective roles of mtDNA and nuclear DNA mutations in COX deficiency, we sequenced the three mitochondrially encoded COX subunits (COXI-III) in a series of 18 patients with isolated COX deficiency, especially as COXI-III code for the catalytic site of the enzyme. We failed to detect any deleterious mutations in this series. Moreover, no mtDNA deletion was observed and sequencing of the flanking tRNA genes involved in the maturation of the COX transcripts failed to detect deleterious mutations as well. The present study supports the view that the disease-causing mutations do not lie in the mt genome but, rather, in the nuclear genes encoding either the COX subunits or the proteins involved in assembly of the complex and suggests a recurrent risk of 25% rather than other modes of inheritance in COX deficiencies.

Cell Nucleus↗

PubMed1983

Conservation and divergence of immunoglobulin VH pseudogenes.

The 12 immunoglobulin VH pseudogenes, that have been characterized to date, differ from most pseudogenes of other multigene families in two aspects: (i) they carry only one (11 cases) or at the most two (1 case) deleterious mutations and (ii) they show no evidence of increased divergence from intact VH genes. We describe here the first immunoglobulin VH pseudogene that does not have these characteristics. This pseudogene accumulated numerous deleterious mutations and diverged considerably from other genes of the VH gene family to which it belongs. In possible contrast to the other VH pseudogenes, this pseudogene seems to be selectively neutral. We discuss the implications of the characterization of this diverged VH pseudogene in relation to our understanding of the genetic mechanisms that generate diversity among germline immunoglobulin VH genes.

Animals↗

PubMed1998

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

PURPOSE: Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS: A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS: Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION: Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

Adult↗

PubMed1996

Accelerated evolution and Muller's rachet in endosymbiotic bacteria.

Many bacteria live only within animal cells and infect hosts through cytoplasmic inheritance. These endosymbiotic lineages show distinctive population structure, with small population size and effectively no recombination. As a result, endosymbionts are expected to accumulate mildly deleterious mutations. If these constitute a substantial proportion of new mutations, endosymbionts will show (i) faster sequence evolution and (ii) a possible shift in base composition reflecting mutational bias. Analyses of 16S rDNA of five independently derived endosymbiont clades show, in every case, faster evolution in endosymbionts than in free-living relatives. For aphid endosymbionts (genus Buchnera), coding genes exhibit accelerated evolution and unusually low ratios of synonymous to nonsynonymous substitutions compared to ratios for the same genes for enterics. This concentration of the rate increase in nonsynonymous substitutions is expected under the hypothesis of increased fixation of deleterious mutations. Polypeptides for all Buchnera genes analyzed have accumulated amino acids with codon families rich in A+T, supporting the hypothesis that substitutions are deleterious in terms of polypeptide function. These observations are best explained as the result of Muller's ratchet within small asexual populations, combined with mutational bias. In light of this explanation, two observations reported earlier for Buchnera, the apparent loss of a repair gene and the overproduction of a chaperonin, may reflect compensatory evolution. An alternative hypothesis, involving selection on genomic base composition, is contradicted by the observation that the speedup is concentrated at nonsynonymous sites.

Animals↗

PubMed1997

Rapid fixation of deleterious alleles can be caused by Muller's ratchet.

Theoretical arguments are presented which suggest that each advance of Muller's ratchet in a haploid asexual population causes the fixation of a deleterious mutation at a single locus. A similar process operates in a diploid, fully asexual population under a wide range of parameter values, with respect to fixation within one of the two haploid genomes. Fixations of deleterious mutations in asexual species can thus be greatly accelerated in comparison with a freely recombining genome, if the ratchet is operating. In a diploid with segregation of a single chromosome, but no crossing over within the chromosome, the advance of the ratchet can be decoupled from fixation if mutations are sufficiently close to recessivity. A new analytical approximation for the rate of advance of the ratchet is proposed. Simulation results are presented that validate the assertions about fixation. The simulations show that none of the analytical approximations for the rate of advance of the ratchet are satisfactory when population size is large. The relevance of these results for evolutionary processes such as Y chromosome degeneration is discussed.

Alleles↗

PubMed2003

Searching for the advantages of virus sex.

Sex (genetic exchange) is a nearly universal phenomenon in biological populations. But this is surprising given the costs associated with sex. For example, sex tends to break apart co-adapted genes, and sex causes a female to inefficiently contribute only half the genes to her offspring. Why then did sex evolve? One famous model poses that sex evolved to combat Muller's ratchet, the mutational load that accrues when harmful mutations drift to high frequencies in populations of small size. In contrast, the Fisher-Muller Hypothesis predicts that sex evolved to promote genetic variation that speeds adaptation in novel environments. Sexual mechanisms occur in viruses, which feature high rates of deleterious mutation and frequent exposure to novel or changing environments. Thus, confirmation of one or both hypotheses would shed light on the selective advantages of virus sex. Experimental evolution has been used to test these classic models in the RNA bacteriophage phi6, a virus that experiences sex via reassortment of its chromosomal segments. Empirical data suggest that sex might have originated in phi6 to assist in purging deleterious mutations from the genome. However, results do not support the idea that sex evolved because it provides beneficial variation in novel environments. Rather, experiments show that too much sex can be bad for phi6; promiscuity allows selfish viruses to evolve and spread their inferior genes to subsequent generations. Here I discuss various explanations for the evolution of segmentation in RNA viruses, and the added cost of sex when large numbers of viruses co-infect the same cell.

Biological Evolution↗

PubMed1999

The age of nonsynonymous and synonymous mutations in animal mtDNA and implications for the mildly deleterious theory.

McDonald/Kreitman tests performed on animal mtDNA consistently reveal significant deviations from strict neutrality in the direction of an excess number of polymorphic nonsynonymous sites, which is consistent with purifying selection acting on nonsynonymous sites. We show that under models of recurrent neutral and deleterious mutations, the mean age of segregating neutral mutations is greater than the mean age of segregating selected mutations, even in the absence of recombination. We develop a test of the hypothesis that the mean age of segregating synonymous mutations equals the mean age of segregating nonsynonymous mutations in a sample of DNA sequences. The power of this age-of-mutation test and the power of the McDonald/Kreitman test are explored by computer simulations. We apply the new test to 25 previously published mitochondrial data sets and find weak evidence for selection against nonsynonymous mutations.

Alleles↗

PubMed1995

Linkage and the limits to natural selection.

The probability of fixation of a favorable mutation is reduced if selection at other loci causes inherited variation in fitness. A general method for calculating the fixation probability of an allele that can find itself in a variety of genetic backgrounds is applied to find the effect of substitutions, fluctuating polymorphisms, and deleterious mutations in a large population. With loose linkage, r, the effects depend on the additive genetic variance in relative fitness, var(W), and act by reducing effective population size by (N/Ne) = 1 + var(W)/2r2. However, tightly linked loci can have a substantial effect not predictable from Ne. Linked deleterious mutations reduce the fixation probability of weakly favored alleles by exp (-2U/R), where U is the total mutation rate and R is the map length in Morgans. Substitutions can cause a greater reduction: an allele with advantage s < scrit = (pi 2/6) loge (S/s) [var(W)/R] is very unlikely to be fixed. (S is the advantage of the substitution impeding fixation.) Fluctuating polymorphisms at many (n) linked loci can also have a substantial effect, reducing fixation probability by exp [square root of 2Kn var(W)/R] [K = -1/E((u-u)2/uv) depending on the frequencies (u,v) at the selected polymorphisms]. Hitchhiking due to all three kinds of selection may substantially impede adaptation that depends on weakly favored alleles.

Genetic Linkage↗

PubMed2000

The origins, patterns and implications of human spontaneous mutation.

The germline mutation rate in human males, especially older males, is generally much higher than in females, mainly because in males there are many more germ-cell divisions. However, there are some exceptions and many variations. Base substitutions, insertion-deletions, repeat expansions and chromosomal changes each follow different rules. Evidence from evolutionary sequence data indicates that the overall rate of deleterious mutation may be high enough to have a large effect on human well-being. But there are ways in which the impact of deleterious mutations can be mitigated.

Female↗