Effect of reproductive compensation and the desire to have male offspring on the incidence of a sex-linked lethal disease.

The effects of reproductive compensation on an X-linked recessive lethal are examined. Complete compensation without regard to the sex of the offspring increases the incidence of female carriers by a factor of 1.5, and of affected males by 1.33. However, if families reproduce until they have a healthy male offspring, the incidence of the X-linked lethal can be increased two or three orders of magnitude. Even only 1% of the population reproducing until a male is born can inflate the incidence of the disease by an order of magnitude, provided this pattern of family planning is culturally inherited. Similarly, reproducing until there is at least one child of each sex increases the incidence of an X-linked lethal. The impact of these types of sex-biased family planning on the fraction of new mutants among affect males is discussed.     

Cultural inheritance of the desire for male offspring and the incidence of a sex‐linked lethal disease

Abstract

This paper studies the effect of having at least one male offspring on a sex‐linked recessive disease and the fraction of affected males due to fresh mutations. The equilibrium frequency of heterozygous females depends not only on the intensity of the reproductive compensation, but also on the time of mutational change. It has been shown that the frequency ranges from 4u without reproductive compensation to √2u or √3u with strict compensation, where u is the mutation rate from the wild type allele to lethal gene. The frequency √2u is achieved when mutation occurs in mature germ cells, whereas, √3u achieved when mutation occurs in early development of germ cells. This increased frequency of heterozygous females due to reproductive compensation reduces considerably the proportion of affected males due to fresh mutation.     

The effect of reproductive compensation on recessive disorders within consanguineous human populations

We investigate the effects of consanguinity and population substructure on genetic health using the UK Asian population as an example. We review and expand upon previous treatments dealing with the deleterious effects of consanguinity on recessive disorders and consider how other factors, such as population substructure, may be of equal importance. For illustration, we quantify the relative risks of recessive lethal disorders by presenting some simple calculations that demonstrate the effect 'reproductive compensation' has on the maintenance of recessive alleles. The results show how reproductive compensation can effectively counteract the purging of deleterious alleles within consanguineous populations. Whereas inbreeding does not elevate the equilibrium frequency of affected individuals, reproductive compensation does. We suggest this effect must be built into interpretations of the incidence of genetic disease within populations such as the UK Asians. Information of this nature will benefit health care workers who inform such communities.     

The effect of a change in mutation rate on the incidence of dominant and X-linked recessive disorders in man

In order to assess the impact on man of a sustained change in mutation rate that might be caused by ionizing radiation or a chemical mutagen in the environment, it is important to determine the current incidence of genetic disease, the rate at which deleterious mutations arise and the number of generations that mutations persist before eliminated by selection. From these data it should be possibel to estimate both the increase in genetic disease in the first generation following the increase in mutation rate, and the rate at which a new equilibrium between mutation and selection would occur. In this paper the results of a survey to determine birth frequency, mutation rate and reproductive fitness for each of the important dominant and X-linked recessive disorders are described. It is estimated that these disorders affect about 0.6% of live-born individuals, including 0.1% of live-borns who carry a newly-arising mutation. These figures are approx. 50% lower than those used by the various committees that have assessed the genetic risk to man form ionizing radiation. If the mutation rate were to permanently double, the frequency of these disorders would be expected in increase in the first generation by 15%, to 0.7% of live-births. The increase in the first 2 generations would be 24% and a 50% increase would occur by the 9th generation. a calculation of the possible increase in dominant and X-linked recessive disorders due to exposure of a population to ionizing radiation indicates that the estimate made in 1977 by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) may be too high by a factor of 2–6 fold.     

Dynamics of inbreeding depression due to deleterious mutations in small populations: mutation parameters and inbreeding rate

A multilocus stochastic model is developed to simulate the dynamics of mutational load in small populations of various sizes. Old mutations sampled from a large ancestral population at mutation-selection balance and new mutations arising each generation are considered jointly, using biologically plausible lethal and deleterious mutation parameters. The results show that inbreeding depression and the number of lethal equivalents due to partially recessive mutations can be partly purged from the population by inbreeding, and that this purging mainly involves lethals or detrimentals of large effect. However, fitness decreases continuously with inbreeding, due to increased fixation and homozygosity of mildly deleterious mutants, resulting in extinctions of very small populations with low reproductive rates. No optimum inbreeding rate or population size exists for purging with respect to fitness (viability) changes, but there is an optimum inbreeding rate at a given final level of inbreeding for reducing inbreeding depression or the number of lethal equivalents. The interaction between selection against partially recessive mutations and genetic drift in small populations also influences the rate of decay of neutral variation. Weak selection against mutants relative to genetic drift results in apparent overdominance and thus an increase in effective size (Ne) at neutral loci, and strong selection relative to drift leads to a decrease in Ne due to the increased variance in family size. The simulation results and their implications are discussed in the context of biological conservation and tests for purging.     

Effects of reproductive compensation and genetic drift on X-linked lethals

A revival of interest in Haldane's equilibrium theory for X-linked lethals has been stimulated by the introduction of accurate tests for the detection of female heterozygotes in Lesch-Nyhan disease. Application of these tests appears to indicate an excess of familial cases. This excess can be attributed to ascertainment bias, a difference in female and male mutation rates, genetic drift, and reproductive compensation. Reproductive compensation will be particularly effective in increasing the proportion of familial cases if (1) birth control is widespread; (2) selection against affected males acts in utero; (3) affected sons show symptoms at an early age; and (4) sons are more highly valued than daughters. We demonstrate how only a few generations of reproductive compensation are sufficient to achieve an approximate equilibrium between selection and mutation showing a high proportion of familial cases. We also discuss the random fluctuations around equilibrium caused by genetic drift.     

Hemochromatosis gene variants in three different ethnic populations: effects of admixture for screening programs

Genetic testing for hemochromatosis may have important implications for diagnosis and screening of the disease. However, the relative importance of mutations in the gene for hereditary hemochromatosis, HFE, may vary among populations, when the mutant allele frequencies and their penetrance in a particular genetic and environmental background are taken into account. We present data on the allele and genotype frequencies and population structure of two HFE genetic variants in three different ethnic groups from a highly mixed urban population (S?o Paulo, Brazil). Allele frequencies for both the C282Y and H63D HFE mutations showed significant differences among the studied populations (for the C282Y mutation, Euro-Brazilian 3.7%, admixed 0.7%, Afro-Brazilian 0.5%; and for the H63D mutation, Euro-Brazilian 20.3%, admixed 13.0%, Afro-Brazilian 6.4). The data substantiate a European origin for these mutations. Furthermore, they provide a basis for a more rational strategic planning of population screening programs for the disease.     

The Effects of a Bottleneck on Inbreeding Depression and the Genetic Load

We study the effects of a population bottleneck on the inbreeding depression and genetic load caused by deleterious mutations in an outcrossing population. The calculations assume that loci have multiplicative fitness effects and that linkage disequilibrium is negligible. Inbreeding depression decreases immediately after a sudden reduction of population size, but the drop is at most only several percentage points, even for severe bottlenecks. Highly recessive mutations experience a purging process that causes inbreeding depression to decline for a number of additional generations. On the basis of available parameter estimates, the absolute fall in inbreeding depression may often be only a few percentage points for bottlenecks of 10 or more individuals. With a very high lethal mutation rate and a very slow population growth, however, the decline may be on the order of 25%. We examine when purging might favor a switch from outbreeding to selfing and find it occurs only under very limited conditions unless population growth is very slow. In contrast to inbreeding depression, a bottleneck causes an immediate increase in the genetic load. Purging causes the load to decline and then overshoot its equilibrium value. The changes are typically modest: the absolute increase in the total genetic load will be at most a few percentage points for bottlenecks of size 10 or more unless the lethal mutation rate is very high and the population growth rate very slow.     

Three new BLM gene mutations associated with Bloom syndrome

Bloom's syndrome (BS) is a rare autosomal recessive disease predisposing patients to all types of cancers affecting the general population. BS cells display a high level of genetic instability, including a 10-fold increase in the rate of sister chromatid exchanges, currently the only objective criterion for BS diagnosis. We have developed a method for screening the BLM gene for mutations based on direct genomic DNA sequencing. A questionnaire based on clinical information, cytogenetic features, and family history was addressed to physicians prescribing BS genetic screening, with the aim of confirming or guiding diagnosis. We report here four BLM gene mutations, three of which have not been described before. Three of the mutations are frameshift mutations, and the fourth is a nonsense mutation. All these mutations introduce a stop codon, and may therefore be considered to have deleterious biological effect. This approach should make it possible to identify new mutations and to correlate them with clinical information.     

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness¹ and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them². This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia³. The male-to-female ratio of mutation rate is estimated at about 4–6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males⁴. A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.     

Beneficial mutations, hitchhiking and the evolution of mutation rates in sexual populations

Natural selection acts in three ways on heritable variation for mutation rates. A modifier allele that increases the mutation rate is (i) disfavored due to association with deleterious mutations, but is also favored due to (ii) association with beneficial mutations and (iii) the reduced costs of lower fidelity replication. When a unique beneficial mutation arises and sweeps to fixation, genetic hitchhiking may cause a substantial change in the frequency of a modifier of mutation rate. In previous studies of the evolution of mutation rates in sexual populations, this effect has been underestimated. This article models the long-term effect of a series of such hitchhiking events and determines the resulting strength of indirect selection on the modifier. This is compared to the indirect selection due to deleterious mutations, when both types of mutations are randomly scattered over a given genetic map. Relative to an asexual population, increased levels of recombination reduce the effects of beneficial mutations more rapidly than those of deleterious mutations. However, the role of beneficial mutations in determining the evolutionarily stable mutation rate may still be significant if the function describing the cost of high-fidelity replication has a shallow gradient.     

Reproductive compensation in the evolution of plant mating systems

Reproductive compensation, the replacement of dead embryos by potentially viable ones, is known to play a major role in the maintenance of deleterious mutations in mammalian populations. However, it has received little attention in plant evolution. Here we model the joint evolution of mating system and inbreeding depression with reproductive compensation. We used a dynamic model of inbreeding depression, allowing for partial purging of recessive lethal mutations by selfing. We showed that reproductive compensation tended to increase the mean number of lethals in a population, but favored self-fertilization by effectively decreasing early inbreeding depression. When compensation depended on the selfing rate, stable mixed mating systems can occur, with low to intermediate selfing rates. Experimental evidence of reproductive compensation is required to confirm its potential importance in the evolution of plant mating systems. We suggest experimental methods to detect reproductive compensation.     

Theory of lethal mutagenesis for viruses

Mutation is the basis of adaptation. Yet, most mutations are detrimental, and elevating mutation rates will impair a population's fitness in the short term. The latter realization has led to the concept of lethal mutagenesis for curing viral infections, and work with drugs such as ribavirin has supported this perspective. As yet, there is no formal theory of lethal mutagenesis, although reference is commonly made to Eigen's error catastrophe theory. Here, we propose a theory of lethal mutagenesis. With an obvious parallel to the epidemiological threshold for eradication of a disease, a sufficient condition for lethal mutagenesis is that each viral genotype produces, on average, less than one progeny virus that goes on to infect a new cell. The extinction threshold involves an evolutionary component based on the mutation rate, but it also includes an ecological component, so the threshold cannot be calculated from the mutation rate alone. The genetic evolution of a large population undergoing mutagenesis is independent of whether the population is declining or stable, so there is no runaway accumulation of mutations or genetic signature for lethal mutagenesis that distinguishes it from a level of mutagenesis under which the population is maintained. To detect lethal mutagenesis, accurate measurements of the genome-wide mutation rate and the number of progeny per infected cell that go on to infect new cells are needed. We discuss three methods for estimating the former. Estimating the latter is more challenging, but broad limits to this estimate may be feasible.     

Revertant Mutation Releases Confined Lethal Mutation,Opening Pandora's Box: A Novel Genetic Pathogenesis

When two mutations, one dominant pathogenic and the other “confining” nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora''s box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (KID) syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient''s mother had the identical misssense mutation which was confined by the nonsense mutation. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.     

Effect of cultural inheritance of reproductive compensation on the incidence of a sex-linked lethal disease

For a sex-linked recessive lethal disease, a model is constructed to study reproductive compensation for having at least one normal male with partial cultural inheritance. The equilibrium frequency of heterozygous females depends on the probability that a female offspring of the compensating parents will not compensate, α, the probability that a female offspring of the non-compensating parents will compensate, β, and the mutation rate, u. When α = 0, the equilibrium frequency of heterozygous females is given by √2u, whereas when α ≠ 0 it is given by 2[{β +(2α + β) (α + β)}/{α(α + β)}]u.Then, the proportion of affected males due to fresh mutations is much smaller than Haldane's estimate of $\text{1}\text{3}$ without reproductive compensation.     

Towards an understanding of the nature and fitness of induced mutations in germ cells of mice: homozygous viability and heterozygous fitness effects of induced specific-locus, dominant cataract and enzyme-activity mutations

A total of 219 specific-locus, 35 dominant cataract and 44 enzyme-activity mutations induced in spermatogonia of mice by radiation or ethylnitrosourea (ENU) treatment were characterized for homozygous viability as well as fitness effects on heterozygous carriers. For all 3 genetic endpoints, the frequency of homozygous lethal mutations was higher in the group of radiation-induced mutations than in the ENU-treatment group. These observations are consistent with the hypothesis that radiation-induced mutations recovered in the mouse are mainly due to small deletions while ENU induces mainly intragenic mutations. The overall fitness of mutant heterozygotes was reduced for the group of radiation-induced specific-locus, dominant cataract and enzyme-activity mutations while the ENU-induced mutations exhibited no reduction in fitness. The fitness reduction of heterozygous carriers for a newly occurring mutation in a population is important in determining the persistence of the mutation in a population, and thus the total number of individuals affected before a mutation is eventually eliminated from the population. For the present results a maximal persistence of 12 generations and a minimal persistence of 3 generations is estimated. These results are consistent with the 6-7-generation persistence time assumed by UNSCEAR (1982) in an estimate of the overall effects of radiation-induced mutations in man.     

Effect of misreported family history on Mendelian mutation prediction models

People with familial history of disease often consult with genetic counselors about their chance of carrying mutations that increase disease risk. To aid them, genetic counselors use Mendelian models that predict whether the person carries deleterious mutations based on their reported family history. Such models rely on accurate reporting of each member's diagnosis and age of diagnosis, but this information may be inaccurate. Commonly encountered errors in family history can significantly distort predictions, and thus can alter the clinical management of people undergoing counseling, screening, or genetic testing. We derive general results about the distortion in the carrier probability estimate caused by misreported diagnoses in relatives. We show that the Bayes factor that channels all family history information has a convenient and intuitive interpretation. We focus on the ratio of the carrier odds given correct diagnosis versus given misreported diagnosis to measure the impact of errors. We derive the general form of this ratio and approximate it in realistic cases. Misreported age of diagnosis usually causes less distortion than misreported diagnosis. This is the first systematic quantitative assessment of the effect of misreported family history on mutation prediction. We apply the results to the BRCAPRO model, which predicts the risk of carrying a mutation in the breast and ovarian cancer genes BRCA1 and BRCA2.     

Mechanisms of reproductive compensation in populations with different types of reproduction

Reproductive compensation mechanisms have been studied in two populations with different reproductive behaviour. In populations with natural reproductive behaviour mechanism of reproductive compensation was shown to be the shortening of the mean intergenetic interval in the female group having excessive (as compared with the mean population value) failures in their pregnancy outcomes (spontaneous abortions, still-births, prereproductive age deaths of children). In family planning populations, however, reproductive compensation mechanisms are: deliberate shortening of the intergenetic interval after pregnancy failure only and deliberate prolongation of actual reproduction. In family planning populations the proportion of females bearing at over 35 was shown to double, due to reproductive compensation.     

BRCA2 gene mutations in Slovenian male breast cancer patients

Male breast cancer (MBC) is a rare disease, comprising less than 1% of breast cancer patients in Slovenia. Some inherited cases are due to the mutations of BRCA1 or BRCA2 genes. There is no information available about the frequency of BRCA gene mutations in Slovenian MBC population. The purpose of this study was to characterize BRCA germline mutations in Slovenian MBC patients. Forty-one patients who were diagnosed with breast cancer at the Institute of Oncology Ljubljana between 1970 and 2006 were proposed to take part in this study. Of them, 27 agreed to follow a genetic counseling session and 25 patients agreed to provide a blood sample for genetic testing. The BRCA1 and BRCA2 genes from the MBC patients were screened for four highly recurrent mutations in the Slovenian population. When an additional breast cancer case or an ovarian cancer was present in the family, a more extended analysis was performed. No BRCA1 mutations were found. A BRCA2 gene mutation was identified in four MBC patients. Three of them carried the Slovenian founder mutation IVS16-2A>G. All four mutations were confined to the patients with a family history of breast cancer. Among the MBC patients with a family history of breast cancer in the first- or second-degree relatives, the frequency of BRCA2 gene mutation was 50%. The median age of the patients with a BRCA2 gene mutation was 60 years, not significantly different from those without a mutation. The BRCA2 mutations were diagnosed in 16% of our MBC patients.     

Aberrations in SMAD family of genes among HNSCC patients

Head and neck cancer is a debilitating disease with several etiological factors. One of the main etiologies to be noticed is the alteration, which is either caused by genetic or environmental factors. Therefore, it is of interest to assess the effect of genetic alterations, especially the non-synonymous mutations of the SMAD gene family and its possible association with HNSCC. Data shows a significant novel mutation in the SMAD gene family in association with head and neck squamous cell carcinoma (HNSCC), which would aid in better diagnosis and treatment planning for cancer.