Biomedical subjects

L A Zhivotovsky

Publications and source records attributed to L A Zhivotovsky.

At least 19 recordsLinked to original sources

PubMed2006

Male amelogenin dropouts: phylogenetic context, origins and implications.

Several commercial PCR multiplex kits incorporate the amelogenin locus for the purpose of human gender identification. Consequently, erroneous results in the electropherogram profile of this locus can carry important forensic implications. In this study, dropout of the amelogenin Y allele was detected in 5 out of 77 phenotypically normal Kathmandu males using the AmpFlSTR Identifiler kit. A battery of male-specific markers including SNPs, STRs, STSs, and a minisatellite were amplified for the five amelogenin null samples in order to delineate the breakpoints of the deletions as well as assess the overall integrity of the Y-chromosome. This study represents the first to examine the haplogroup affiliation of the AMGY deletions. The analyses performed suggest a single origin for the five deletions as indicated by their allocation to a specific Y-haplogroup (J2b2-M241), related Y-STR haplotypes and identical regional localization of breakpoints. The age estimated from the microsatellite variation for the amelogenin deletions (if they are associated by descent) is approximately 6.5+/-3.3 ky, younger than the previously reported related age of the M241 haplogroup representatives (13-14 ky). Our data in combination with previous publications suggest a concentration of afflicted individuals in the Indian subcontinent, possibly as a result of common ancestry. The elevated incidence of the amelogenin dropout in these populations accentuates the need to utilize other loci for gender determination in order to obtain an accurate set of inclusion criteria in forensic casework.

Alleles↗

PubMed2004

Consanguinity, caste and deaf-mutism in Punjab, 1921.

The effects of religion, population sub-division and geography on the prevalence of deaf-mutism were investigated using information collected in the 1921 Census of Punjab. The total sample size was 9.36 million, and comprised data on thirteen Hindu castes, seventeen Muslim biraderis and two Sikh castes. A two-way analysis of variance comparing males in Hindu castes in which consanguineous marriage was prohibited, with males in Muslim biraderis which favoured first cousin marriage, indicated major differences with respect to the patterns of deaf-mutism within each religion. In the Muslim population 9.1% of the relative variation in the prevalence of deaf-mutism was inter-biraderi, 36.8% between geographical regions, and 48.8% an interaction between biraderi and region, whereas among Hindus 46.8% of the observed variation was inter-caste, 12.8% inter-region and 33.6% due to caste region interaction. From a wider disease perspective the results obtained with the Hindu community indicate the significant genetic differentiation associated with caste endogamy. As the overwhelming majority of Hindu marriages continue to be within-caste, it can be predicted that similar levels of inter-caste differences in disease frequency currently exist. By comparison, the lower level of inter-biraderi variation among Muslims is probably indicative of the dissolution of pre-existing caste boundaries and the resultant gene pool mixing that followed the large-scale conversion of Hindus to Islam during Muslim rule in North India from the 13th to the 19th centuries.

Catchment Area, Health↗

PubMed2001

The forensic DNA implications of genetic differentiation between endogamous communities.

In many indigenous minority populations, and among migrants from Asian and African populations now resident in western Europe, North America and Australia, there is a strong tradition of endogamy and a preference for consanguineous unions. These marriage practices can result in F(ST) values greatly in excess of the maximum value (0.01) currently recommended for forensic DNA purposes under guidelines established by the National Research Council (NRC) of the USA. To examine the possible extent of deviation from this accepted norm, three co-resident Pakistani communities were studied using 10 autosomal dinucleotide markers and six tetranucleotide markers on the Y-chromosome. The mean population subdivision coefficient (FST) value was 0.13 for the autosomal loci, and Y-chromosome loci exhibited even stronger differentiation with unique alleles identified in all three communities. The data indicate that even when sub-populations are virtually indistinguishable in terms of anthropology, geography, ethnicity or culture, they may still exhibit major genetic differentiation. Where significant population stratification is known to exist, more detailed genetic databases should be developed for forensic DNA purposes, based on reference data from each of the appropriate sub-populations and not on random or combined samples.

Consanguinity↗

PubMed2001

Genetic sampling error of distance (delta(mu))2 and variation in mutation rate among microsatellite loci.

An expression is obtained for the time-dependent variance of the microsatellite genetic distance (delta(mu))2 when the mutation rate is allowed to vary randomly among loci. An estimator is presented for the coefficient of variation, C(w), in the mutation rate. Estimated values of C(w) from genetic distances between African and non-African populations were less than 100%. Caveats to this conclusion are discussed.

Humans↗

PubMed2001

Estimating divergence time with the use of microsatellite genetic distances: impacts of population growth and gene flow.

Genetic distances play an important role in estimating divergence time of bifurcated populations. However, they can be greatly affected by demographic processes, such as migration and population dynamics, which complicate their interpretation. For example, the widely used distance for microsatellite loci, (deltamu)2, assumes constant population size, no gene flow, and mutation-drift equilibrium. It is shown here that (deltamu)2 strongly underestimates divergence time if populations are growing and/or connected by gene flow. In recent publications, the average estimate of divergence time between African and non-African populations obtained by using (deltamu)2 is about 34,000 years, although archaeological data show a much earlier presence of modern humans out of Africa. I introduce a different estimator of population separation time based on microsatellite statistics, T(D), that does not assume mutation-drift equilibrium, is independent of population dynamics in the absence of gene flow, and is robust to weak migration flow for growing populations. However, it requires a knowledge of the variance in the number of repeats at the beginning of population separation, V(0). One way to overcome this problem is to find minimal and maximal bounds for the variance and thus obtain the earliest and latest bounds for divergence time (this is not a confidence interval, and it simply reflects an uncertainty about the value of V(0) in an ancestral population). Another way to avoid the uncertainty is to choose from among present populations a reference whose variation is presumably close to what it might have been in an ancestral population. A different approach for using T(D) is to estimate the time difference between adjacent nodes on a phylogenetic population tree. Using data on variation at autosomal short tandem repeat loci with di-, tri-, and tetranucleotide repeats in worldwide populations, T(D) gives an estimate of 57,000 years for the separation of the out-of-Africa branch of modern humans from Africans based on the value of V(0) in the Southern American Indian populations; the earliest bound for this event has been estimated to be about 135,000 years. The data also suggest that the Asian and European populations diverged from each other about 20,000 years, after the occurrence of the out-of-Africa branch.

Animals↗

PubMed2000

Mobile elements and chromosomal evolution in the virilis group of Drosophila.

Species of the virilis group of Drosophila differ by multiple inversions and chromosome fusions that probably accompanied, or led to, speciation. Drosophila virilis has the primitive karyotype for the group, and natural populations are exceptional in having no chromosomal polymorphisms. We report that the genomic locations of Penelope and Ulysses transposons are nonrandomly distributed in 12 strains of D. virilis. Furthermore, Penelope and Ulysses insertion sites in D. virilis show a statistically significant association with the breakpoints of inversions found in other species of the virilis group. Sixteen newly induced chromosomal rearrangements were isolated from the progeny of D. virilis hybrid dysgenic crosses, including 12 inversions, 2 translocations, and 2 deletions. Penelope and Ulysses were associated with the breakpoints of over half of these new rearrangements. Many rearrangement breakpoints also coincide with the chromosomal locations of Penelope and Ulysses insertions in the parental strains and with breakpoints of inversions previously established for other species of the group. Analysis of homologous sequences from D. virilis and Drosophila lummei indicated that Penelope insertion sites were closely, but not identically, located at the nucleotide sequence level. Overall, these results indicate that Penelope and Ulysses insert in a limited number of genomic locations and are consistent with the possibility that these elements play an important role in the evolution of the virilis species group.

Animals↗

PubMed2000

A genome-based study of consanguinity in three co-resident endogamous Pakistan communities.

In a study based on 173 individuals drawn from three endogamous, co-resident communities in the province of Punjab, the Awan, Khattar and Rajpoot, an analysis of 10 autosomal single tandem repeats on chromosomes 13 and 15 revealed distinctive genetic profiles in each community. A total of 99 different alleles were detected, with 28 alleles (28.3%) shared by all three communities. The mean private allele frequency was 7.7%. There was a reduction in heterozygosity and high average inbreeding effects (FIS and/or HS), particularly in the Awan, indicating genetic isolation and a high cumulative level of autozygosity. Genotyping with eight Y-chromosome STRs resulted in the construction of six haplotypes, one each for the Awan and the Khattar but four for the Rajpoot, suggesting marked variation in the patterns of male founder effects in the history of each community. The lower than expected levels of homozygosity observed at a number of loci may be indicative of cosegregation of the STRs with nearby early development genes subject to selection.

Alleles↗

PubMed2000

Microsatellite evolution in modern humans: a comparison of two data sets from the same populations.

We genotyped 64 dinucleotide microsatellite repeats in individuals from populations that represent all inhabited continents. Microsatellite summary statistics are reported for these data, as well as for a data set that includes 28 out of 30 loci studied by Bowcock et al. (1994) in the same individuals. For both data sets, diversity statistics such as heterozygosity, number of alleles per locus, and number of private alleles per locus produced the highest values in Africans, intermediate values in Europeans and Asians, and low values in Americans. Evolutionary trees of populations based on genetic distances separated groups from different continents. Corresponding trees were topologically similar for the two data sets, with the exception that the (deltamu)2 genetic distance reliably distinguished groups from different continents for the larger data set, but not for the smaller one. Consistent with our results from diversity statistics and from evolutionary trees, population growth statistics S k and beta, which seem particularly useful for indicating recent and ancient population size changes, confirm a model of human evolution in which human populations expand in size and through space following the departure of a small group from Africa.

Alleles↗

PubMed2000

The strength of the selection barrier between populations.

Genetic differences among populations exposed to selection form barriers against genetic exchange by mortality among hybrids. The strength of such a selection barrier, with which one (recipient) population reacts against immigration from another (donor) population, may be measured as the cumulative mean fitness of hybrids and their descendants relative to the fitness of the recipient population. Previous work analysed a case of weak selection with pairwise epistatic interactions by assuming small genetic distance between two populations in contact. The present study allows large genetic difference between the donor and recipient populations and considers weak multilocus selection with arbitrary epistatic interactions between two or more linked loci. An approximate analytical expression for the barrier strength is obtained as an expansion in which the strength of selection plays the role of a small parameter. It is shown that allele frequencies and gametic linkage disequilibria contribute in different ways to the strength of the selection barrier.

Models, Genetic↗

PubMed2000

Human population expansion and microsatellite variation.

Polymorphisms at di-, tri-, and tetranucleotide microsatellite loci have been analyzed in 14 worldwide populations. A statistical index of population expansion, denoted S(k), is introduced to detect historical changes in population size using the variation at the microsatellites. The index takes the value 0 at equilibrium with constant population size and is positive or negative according to whether the population is expanding or contracting, respectively. The use of S(k) requires estimation of properties of the mutation distribution for which we use both family data of Dib et al. for dinucleotide loci and our population data on tri- and tetranucleotide loci. Statistical estimates of the expansion index, as well as their confidence intervals from bootstrap resampling, are provided. In addition, a dynamical analysis of S(k) is presented under various assumptions on population growth or decline. The studied populations are classified as having high, intermediate, or low values of S(k) and genetic variation, and we use these to interpret the data in terms of possible population dynamics. Observed values of S(k) for samples of di-, tri-, and tetranucleotide data are compatible with population expansion earlier than 60,000 years ago in Africa, Asia, and Europe if the initial population size before the expansion was on the order of 500. Larger initial population sizes force the lower bound for the time since expansion to be much earlier. We find it unlikely that bottlenecks occurred in Central African, East Asian, or European populations, and the estimated expansion times are rather similar for all of these populations. This analysis presented here suggests that modern human populations departed from Africa long before they began to expand in size. Subsequently, the major groups (the African, East Asian, and European groups) started to grow at approximately same time. Populations of South America and Oceania show almost no growth. The Mbuti population from Zaire appears to have experienced a bottleneck during its expansion.

Animals↗

PubMed1999

Mitochondrial DNA sequence diversity in Russians.

The article presents the results of the first regular study of Russian populations by sequencing the control region of mitochondrial DNA (mtDNA). The sequenced region is the most variable on mtDNA molecule and is commonly used for population and evolutionary studies. Russians form one of the largest ethnic groups (more than 129 million). However, their genetic diversity had only been characterized with RFLP and biochemical markers, although there are already established mtDNA sequence databases for many ethnic groups of the world. We have obtained sequence data from 103 individuals living in three Russian regions: Kostroma, Kursk, and Rjazan. The sequenced fragment analyzed is 360 bp in length (positions from 16024 to 16383). Fifty nine nucleotide positions have been found polymorphic in Russians, among those were 57 transitions and two transversions. One individual is found having two insertions of two cytosines between positions 16184 and 16193. Among 64 different mitotypes identified in the study 52 were unique in these samples. The index of genetic diversity (Nei, 1987) for Russians is 0.96. This value is within the established range for European populations (0.93 to 0.98). Genetic distances calculated from our data show that Russians form a cluster with Germans, Bulgarians, Swedes, Estonians, and Volgo-Finns are more distant from Karelians and Finns, and much more differ from Turks and especially Mongolians.

Base Sequence↗

PubMed1999

Estimating population structure in diploids with multilocus dominant DNA markers.

Multilocus DNA markers [random amplified polymorphic DNA (RAPDs), amplified fragment length polymorphism (AFLPs)] are important for population studies because they reveal many polymorphic loci distributed over the genome. The markers are dominant, that is two phenotypes are distinguished at each locus, with a band and with no band. The latter one represents null-homozygotes with unamplified, recessive null-alleles. The frequency of a null-allele can be estimated by taking the square root of the fraction of individuals with no band. Lynch and Milligan (1994) have suggested a modified procedure that reduces bias introduced by the square-root transform. However, the procedure recommends to ignore those samples in which fewer than four null-homozygotes are observed. This may lead to significant bias in estimates of genetic diversity. In this study, I introduce a Bayesian approach to estimation of null-allele frequencies for dominant DNA markers. It follows from computer simulations and data on two conifer species that the Bayesian method gives nearly unbiased estimates of heterozygosity, genetic distances and F-statistics. The influence of a prior distribution and departure from Hardy-Weinberg proportions on the estimates is also considered.

Alleles↗

PubMed1999

A new genetic distance with application to constrained variation at microsatellite loci.

Genetic variation at microsatellite loci is supposed to be constrained within some range in allele size. In this case, the average-square distance (delta mu)2 between two diverged populations moves asymptotically around and underestimates the time since the populations had split. A distance based on the between-locus correlation in the mean repeat scores, DR, is introduced. Numerical simulations show that DR is a linear function of time if the constraints are approximated by a linear centripetal force, which might be due to mutation bias toward a definite range or be caused both by directional mutation bias toward larger allele size and by selection against the greater number of repeats.

Alleles↗

PubMed1998

Migration versus mutation in the evolution of recombination under multilocus selection.

We use modifier theory to compare the evolution of recombination under mutation-selection and migration-selection balance models. Recombination between loosely linked loci subject to weak multilocus selection is controlled by the genotype at a selectively neutral modifier locus. We show that the success of a new modifier depends on the sign and amount of epistasis as well as on the linkage of the modifier locus to the loci under selection. With both migration and mutation, for recombination to increase requires negative (synergistic) epistasis. When epistasis is sufficiently weak, increased recombination is always favoured under mutation-selection balance and never under migration-selection balance. With stronger negative epistasis, there exists a critical recombination value. In this case, a recombination-increasing allele invades the population under mutation-selection balance if its recombination rate with the major loci is less than the critical recombination value, whereas with weak migration it must be above this value. These results are the same for haploid and diploid populations.

Biological Evolution↗

PubMed1998

Stress temperatures and quantitative variation in Drosophila melanogaster.

Using an isofemale line analysis, we analysed the consequences of extreme rearing temperatures for genetic variation in quantitative characters in Drosophila melanogaster. Three types of characters were used: life history (viability and developmental time), body size (thorax length and wing length) and meristic (number of sternopleural chaetae and number of arista branches). Phenotypic variation significantly increased under stress conditions in all morphological characters studied; for viability, it increased at the low stress temperature. Genetic variation, measured by the coefficient of intraclass correlation, was generally higher at both low and high stress temperatures for thorax length and sternopleural chaeta number. For wing length and viability, genetic variation was higher at the low extreme temperature. No consistent trend was found for genetic variation in arista branch number and developmental time. Our results agree with the hypothesis that genetic variation is increased in stressful environments. A possible mechanism underlying this phenomenon is briefly discussed.

Animals↗

PubMed1997

Environmental stress and evolution: a theoretical study.

A haploid population subject to recurrent deleterious mutations and two environments that provide two different profiles of selection coefficients over loci are modeled. The population is supposed to inhabit one "home" environment where it evolves the corresponding genetic constitution. One generation of the population is then exposed to the second, "foreign" environment. The decline in the mean population fitness is considered as a measure of stress in the population caused by the foreign environment. I define the relative strength of stress as 1 minus the ratio of the mean fitnesses in the foreign and home environments, and give the corresponding analytical expression. The stress strength is composed of three different contributors: the environmental component of stress, which is determined by purely external, non-genetic factors of the foreign environment (its carrying capacity), and two genetic components. The latter consists of the environment x genetic component, caused by the direct influence of the foreign environment on selection coefficients, and of the evolutionary component that is due to the adaptation of the population to the home environment. Among others, it is shown that even if the home and foreign environments were equivalent, so that both the environmental and environmental x genetic components of stress were absent, stress would still occur in the foreign environment due to the evolutionary component. The model also predicts that stressful foreign environments cause an increase in the genotypic variance of fitness. Some other features of population variability in stressful environments are discussed. A general conclusion that can be drawn from this model is that a certain environment may be claimed as stressful only if considered with respect to both a given population and the environment in which the population has evolved.

Animals↗

PubMed1997

Biased mutations and microsatellite variation.

Mutation bias is one of the forces that may constrain the variation at microsatellite loci. Here, we study the dynamics of population statistics and the genetic distance between two populations under multiple stepwise mutations with linear bias and random drift. Expressions are derived for these statistics as functions of time, as well as at mutation-drift equilibrium. Applying these expressions to published data on humans and chimpanzees, the regression coefficient of mutation bias on allele size was estimated to be at least between -0.0064 and -0.013. The assumption of mutational bias produces larger estimates of divergence times than are obtained in its absence; in particular, the time of split between African and non-African human populations is estimated to be between 183,000 and 222,000 years, assuming one-step mutations and no selection. With multistep mutations, the divergence time is estimated to be lower.

Animals↗

PubMed1996

Fitness patterns and phenotypic plasticity in a spatially heterogeneous environment.

We analyse patterns of the means and variances of genotypic fitnesses across different niches in a randomly mating haploid population. The population inhabits a spatially heterogeneous environment where it is subject to mutation and weak multilocus additive selection, with different election coefficients in different niches. Approximate analytical expressions are derived for the stationary mean and variance of genotypic fitnesses among the niches in terms of environmental and genetic parameters. As a special case, we analyse an environment described by a variable t, distributed among the niches with mean t(star) and variance D(star) and quadratic decrease in correlation between environments as a function of the difference in values of t. If the niches have the same qualities, the mean and variance of genotypic fitnesses evolve to be quadratic functions of t that achieve their maximum and minimum, respectively, at t(star). With unequal niche qualities, these are non-polynomial functions that attain their extrema at different, usually intermediate values of t, although the coefficient of variation of the genotypic fitnesses still attains its minimum near t(star). The functions involve the total mutation rate, the combination of the loci to genotypic fitnesses, and the frequency and quality distributions of the niches. Thus, for this relatively simple model the norms of reaction may be calculated in terms of the detailed properties of the environmental heterogeneity, and the genetic system.

Biological Evolution↗