Departure from neutrality at the mitochondrial NADH dehydrogenase subunit 2 gene in humans,but not in chimpanzees.

To test whether patterns of mitochondrial DNA (mtDNA) variation are consistent with a neutral model of molecular evolution, nucleotide sequences were determined for the 1041 bp of the NADH dehydrogenase subunit 2 (ND2) gene in 20 geographically diverse humans and 20 common chimpanzees. Contingency tests of neutrality were performed using four mutational categories for the ND2 molecule: synonymous and nonsynonymous mutations in the transmembrane regions, and synonymous and nonsynonymous mutations in the surface regions. The following three topological mutational categories were also used: intraspecific tips, intraspecific interiors, and interspecific fixed differences. The analyses reveal a significantly greater number of nonsynonymous polymorphisms within human transmembrane regions than expected based on interspecific comparisons, and they are inconsistent with a neutral equilibrium model. This pattern of excess nonsynonymous polymorphism is not seen within chimpanzees. Statistical tests of neutrality, such as TAJIMA''s D test, and the D and F tests proposed by FU and LI, indicate an excess of low frequency polymorphisms in the human data, but not in the chimpanzee data. This is consistent with recent directional selection, a population bottleneck or background selection of slightly deleterious mutations in human mtDNA samples. The analyses further support the idea that mitochondrial genome evolution is governed by selective forces that have the potential to affect its use as a "neutral" marker in evolutionary and population genetic studies.     

Historical and Contemporary DNA Indicate Fisher Decline and Isolation Occurred Prior to the European Settlement of California

Establishing if species contractions were the result of natural phenomena or human induced landscape changes is essential for managing natural populations. Fishers (Martes pennanti) in California occur in two geographically and genetically isolated populations in the northwestern mountains and southern Sierra Nevada. Their isolation is hypothesized to have resulted from a decline in abundance and distribution associated with European settlement in the 1800s. However, there is little evidence to establish that fisher occupied the area between the two extant populations at that time. We analyzed 10 microsatellite loci from 275 contemporary and 21 historical fisher samples (1880–1920) to evaluate the demographic history of fisher in California. We did not find any evidence of a recent (post-European) bottleneck in the northwestern population. In the southern Sierra Nevada, genetic subdivision within the population strongly influenced bottleneck tests. After accounting for genetic subdivision, we found a bottleneck signal only in the northern and central portions of the southern Sierra Nevada, indicating that the southernmost tip of these mountains may have acted as a refugium for fisher during the anthropogenic changes of the late 19^th and early 20^th centuries. Using a coalescent-based Bayesian analysis, we detected a 90% decline in effective population size and dated the time of decline to over a thousand years ago. We hypothesize that fisher distribution in California contracted to the two current population areas pre-European settlement, and that portions of the southern Sierra Nevada subsequently experienced another more recent bottleneck post-European settlement.     

Polymorphism and Locus-Specific Effects on Polymorphism at Microsatellite Loci in Natural Drosophila Melanogaster Populations

We have studied the natural variation at microsatellite loci in two African and five non-African populations of Drosophila melanogaster. Ten dinucleotide simple sequence loci were cloned from chromosomally mapped P1 clones and typed for single individuals from isofemale lines of the respective populations. We find that the African populations harbor the largest degree of diversity, while the non-African populations show a lower diversity. This supports previous results that D. melanogaster originated in Africa and spread across the rest of the world in historic times. Using genetic distance measures, we find also a distinct population subdivision between the non-African populations. Most interestingly, we find for some loci in some populations a strongly reduced variability, which cannot be explained by bottleneck effects. Employing a conservative test based on the variance in repeat number, we find that at least one locus in one population deviates significantly from the expectations of mutation-drift equilibrium. We suggest that this may be due to a recent selective sweep in this chromosomal region that may have been caused by a linked locus that was involved in local adaptation of the population.     

Population history in Arabidopsis halleri using multilocus analysis

A. halleri is a psuedometallophyte with a patchy distribution in Europe and is often spread by human activity. To determine the population history and whether this history is consistent with potential human effects, we surveyed nucleotide variation using 24 loci from 12 individuals in a large A. halleri population. The means of total and silent nucleotide variation (θ_W) are within the range expected for the species. The population genetic neutrality tests Tajima’s D and Wall’s B had significant composite results rejecting panmixia, and Approximate Bayesian Computation analysis revealed that a subdivision model better explained the variation than the standard neutral model, refugia (or admixture), bottleneck or change of population size models. A categorical regression analysis further supports the subdivision model, and under the subdivision model, the neutrality tests are no longer significant. The best support was for two source populations, a situation consistent with the mixing of two populations possibly mediated by human activity. This scenario might limit the genetic diversity and adaptive potential of the population. The non‐neutral population variation described here should be considered in bioinformatic searches for adaptation.     

Detecting directional selection in the presence of recent admixture in African-Americans

We investigate the performance of tests of neutrality in admixed populations using plausible demographic models for African-American history as well as resequencing data from African and African-American populations. The analysis of both simulated and human resequencing data suggests that recent admixture does not result in an excess of false-positive results for neutrality tests based on the frequency spectrum after accounting for the population growth in the parental African population. Furthermore, when simulating positive selection, Tajima's D, Fu and Li's D, and haplotype homozygosity have lower power to detect population-specific selection using individuals sampled from the admixed population than from the nonadmixed population. Fay and Wu's H test, however, has more power to detect selection using individuals from the admixed population than from the nonadmixed population, especially when the selective sweep ended long ago. Our results have implications for interpreting recent genome-wide scans for positive selection in human populations.     

Whole‐genome sequencing of two North American Drosophila melanogaster populations reveals genetic differentiation and positive selection

The prevailing demographic model for Drosophila melanogaster suggests that the colonization of North America occurred very recently from a subset of European flies that rapidly expanded across the continent. This model implies a sudden population growth and range expansion consistent with very low or no population subdivision. As flies adapt to new environments, local adaptation events may be expected. To describe demographic and selective events during North American colonization, we have generated a data set of 35 individual whole‐genome sequences from inbred lines of D. melanogaster from a west coast US population (Winters, California, USA) and compared them with a public genome data set from Raleigh (Raleigh, North Carolina, USA). We analysed nuclear and mitochondrial genomes and described levels of variation and divergence within and between these two North American D. melanogaster populations. Both populations exhibit negative values of Tajima's D across the genome, a common signature of demographic expansion. We also detected a low but significant level of genome‐wide differentiation between the two populations, as well as multiple allele surfing events, which can be the result of gene drift in local subpopulations on the edge of an expansion wave. In contrast to this genome‐wide pattern, we uncovered a 50‐kilobase segment in chromosome arm 3L that showed all the hallmarks of a soft selective sweep in both populations. A comparison of allele frequencies within this divergent region among six populations from three continents allowed us to cluster these populations in two differentiated groups, providing evidence for the action of natural selection on a global scale.     

An investigation of the statistical power of neutrality tests based on comparative and population genetic data

In this report, we investigate the statistical power of several tests of selective neutrality based on patterns of genetic diversity within and between species. The goal is to compare tests based solely on population genetic data with tests using comparative data or a combination of comparative and population genetic data. We show that in the presence of repeated selective sweeps on relatively neutral background, tests based on the d(N)/d(S) ratios in comparative data almost always have more power to detect selection than tests based on population genetic data, even if the overall level of divergence is low. Tests based solely on the distribution of allele frequencies or the site frequency spectrum, such as the Ewens-Watterson test or Tajima's D, have less power in detecting both positive and negative selection because of the transient nature of positive selection and the weak signal left by negative selection. The Hudson-Kreitman-Aguadé test is the most powerful test for detecting positive selection among the population genetic tests investigated, whereas McDonald-Kreitman test typically has more power to detect negative selection. We discuss our findings in the light of the discordant results obtained in several recently published genomic scans.     

Geographical delimitation of a partial selective sweep in African Drosophila melanogaster

Positive selection leaves characteristic footprints on DNA variation but detecting such patterns is challenging as the age, the intensity and the mode of selection as well as demography and evolutionary parameters (mutation and recombination rates) all play roles and these are difficult to disentangle. We recorded nucleotide variation in a sample of isogenic chromosomes from a western African population of Drosophila melanogaster at a locus (Fbp2) for which a partial selective sweep had previously been reported. We compared this locus to four other genes from the same chromosomes and from a European and an East African population. Then, we assessed Fbp2 variation in a sample of 370 chromosomes covering a comprehensive geographic sampling of 16 African localities. The signature of selection was tested while accounting for the demographic history of the populations. We found a significant signal of selection in two West African localities including Ivory Coast. Variation at Fpb2 would thus represent a case of an ongoing selective sweep in the range of this species. A weaker, nonsignificant, signal of selection was, however, apparent in some other populations, thus leaving open several possibilities: (i) the selective sweep originated in Ivory Coast and has spread to the rest of the continent; (ii) several African populations report the signature of a selective event having occurred in an ancestral population; (iii) this genome region is subject to independent selective events in African populations; and (iv) A neutral scenario with population subdivision and local bottleneck cannot be fully excluded to explain the molecular patterns observed in some populations.     

A selective sweep in the chloroplast DNA of dioecious silene (section Elisanthe)

Gene flow occurs predominantly via pollen in angiosperms, leading to stronger population subdivision for maternally inherited markers, relative to paternally or biparentally inherited genes. In contrast to this trend, population subdivision within Silene latifolia and S. dioica, as well as subdivision between the two species, is substantially lower in maternally inherited chloroplast genes compared to paternally inherited Y-linked genes. A significant frequency spectrum bias toward rare polymorphisms and a significant loss of polymorphism in chloroplast genes compared to Y-linked and autosomal genes suggest that intra- and inter-specific subdivision in the chloroplast DNA may have been eroded by a selective sweep that has crossed the S. latifolia and S. dioica species boundary.     

New Statistical Tests of Neutrality for DNA Samples from a Population

The purpose of this paper is to develop statistical tests of the neutral model of evolution against a class of alternative models with the common characteristic of having an excess of mutations that occurred a long time ago or a reduction of recent mutations compared to the neutral model. This class of population genetics models include models for structured populations, models with decreasing effective population size and models of selection and mutation balance. Four statistical tests were proposed in this paper for DNA samples from a population. Two of these tests, one new and another a modification of an existing test, are based on EWENS'' sampling formula, and the other two new tests make use of the frequencies of mutations of various classes. Using simulated samples and regression analyses, the critical values of these tests can be computed from regression equations. This approach for computing the critical values of a test was found to be appropriate and quite effective. We examined the powers of these four tests using simulated samples from structured populations, populations with linearly decreasing sizes and models of selection and mutation balance and found that they are more powerful than existing statistical tests of the neutral model of evolution.     

Selective sweeps for recessive alleles and for other modes of dominance

A selective sweep describes the reduction of linked genetic variation due to strong positive selection. If s is the fitness advantage of a homozygote for the beneficial allele and h its dominance coefficient, it is usually assumed that h = 1/2, i.e. the beneficial allele is co-dominant. We complement existing theory for selective sweeps by assuming that h is any value in [0, 1]. We show that genetic diversity patterns under selective sweeps with strength s and dominance 0 < h < 1 are similar to co-dominant sweeps with selection strength 2hs. Moreover, we focus on the case h = 0 of a completely recessive beneficial allele. We find that the length of the sweep, i.e. the time from occurrence until fixation of the beneficial allele, is of the order of \({\sqrt{N/s}}\) generations, if N is the population size. Simulations as well as our results show that genetic diversity patterns in the recessive case h = 0 greatly differ from all other cases.     

Statistical properties of the variation at linked microsatellite loci: implications for the history of human Y chromosomes [published erratum appears in Mol Biol Evol 1997 Mar;14(3):354]

It has recently been suggested that observed levels of variation at microsatellite loci can be used to infer patterns of selection in genomes and to assess demographic history. In order to evaluate the feasibility of these suggestions it is necessary to know something about how levels of variation at microsatellite loci are expected to fluctuate due simply to stochasticity in the processes of mutation and inheritance (genetic sampling). Here we use recently derived properties of the stepwise mutation model to place confidence intervals around the variance in repeat score that is expected at mutation-drift equilibrium and outline a statistical test for whether an observed value differs significantly from expectation. We also develop confidence intervals for the time course of the buildup of variation following a complete elimination of variation, such as might be caused by a selective sweep or an extreme population bottleneck. We apply these methods to the variation observed at human Y-specific microsatellites. Although a number of authors have suggested the possibility of a very recent sweep, our analyses suggest that a sweep or extreme bottleneck is unlikely to have occurred anytime during the last approximately 74,000 years. To generate this result we use a recently estimated mutation rate for microsatellite loci of 5.6 x 10(-4) along with the variation observed at autosomal microsatellite loci to estimate the human effective population size. This estimate is 18,000, implying an effective number of 4,500 Y chromosomes. One important general conclusion to emerge from this study is that in order to reject mutation-drift equilibrium at a set of linked microsatellite loci it is necessary to have an unreasonably large number of loci unless the observed variance is far below that expected at mutation-drift equilibrium.      

Genetic Divergence of Orangutan Subspecies (Pongo pygmaeus)

Microsatellites and mitochondrial DNA sequences were studied for the two subspecies of orangutans (Pongo pygmaeus), which are located in Borneo (P. p. pygmaeus) and Sumatra (P. p. abelii), respectively. Both subspecies possess marked genetic diversity. Genetic subdivision was identified within the Sumatran orangutans. The genetic differentiation between the two subspecies is highly significant for ND5 region but not significant for 16s rRNA or microsatellite data by exact tests, although F _ST estimates are highly significant for these markers. Divergence time between the two subspecies is approximately 2.3 ± 0.5 million years ago (MYA) estimated from our data, much earlier than the isolation of their geological distribution. Neither subspecies underwent a recent bottleneck, though the Sumatran subspecies might have experienced expansion approximately 82,000 years ago. The estimated effective population sizes for both subspecies are on the order of 10⁴. Our results contribute additional information that may be interpreted in the context of orangutan conservation efforts. Received: 13 June 2000 / Accepted: 30 January 2000     

Molecular Analysis of an Allozyme Cline: Alcohol Dehydrogenase in Drosophila Melanogaster on the East Coast of North America

Clines may either be selectively maintained or be the by-product of nonadaptive processes related to population structure and history. Drosophila melanogaster populations on the east coast of North America show a latitudinal cline in the frequencies of two common electrophoretically distinguishable alleles at the alcohol dehydrogenase locus (Adh), designated Adh-S and Adh-F. This cline may either be adaptive or an artifact of a possible recent dual founding of North American D. melanogaster populations in which frequencies of Adh alleles differed between founder populations. By means of a high resolution restriction-mapping technique, we studied the distribution of 113 haplotypes derived from 44 polymorphic DNA markers within the Adh region in 1533 individuals from 25 populations throughout the cline. We found significant clinal differentiation at the polymorphisms determining the mobility-difference causing amino acid replacement between Adh-F and Adh-S alleles. Hitchhiking was limited, despite extensive linkage disequilibrium, and other sites did not vary clinally. Such a pattern of differentiation implies that selection is responsible for the cline. To investigate whether selection acts only on the Adh-F/S site, we performed a ``selective equivalence'''' test under the assumption that all variability within the specified allelic class is selectively neutral. This revealed selective equivalence among Adh-S-bearing haplotypes, whose frequencies showed no differentiation throughout the cline, implying high levels of frequency-homogenizing gene flow. Geographical heterogeneity among Adh-F-bearing haplotypes implied the action of selection on one or more additional variants in linkage disequilibrium with Adh-F. In a further study of a subset of the data (n = 1076 from 18 populations), we found a combined insertion/deletion polymorphism, designated &1, located in the 5'' adult intron and in linkage disequilibrium with Adh-F, to show more marked clinal variation than Adh-F/S. Although the unequivocal identification of the precise target(s) of selection requires further study, we suggest that clinal selection may be acting epistatically on the Adh-F/S and &1 polymorphisms.     

Signatures of demographic bottlenecks in European wolf populations

Monitoring the loss of genetic diversity in wild populations after a bottleneck event is a priority in conservation and management plans. Here, we used diverse molecular markers to search for signatures of demographic bottlenecks in two wolf populations; an isolated population from the Iberian Peninsula and a non-isolated population from European Russia. Autosomal, mtDNA and Y-chromosomal diversity and the effective population size (N_e) were significantly lower in the Iberian population. Neutrality tests using mtDNA sequences, such as R_2, Fu and Li’s F*, Tajima’s D and Fu’s F_s, were positively significant in the Iberian population, suggesting a population decline, but were not significant for the Russian population, likely due to its larger effective population size. However, three tests using autosomal data confirmed the occurrence of the genetic bottleneck in both populations. The M-ratio test was the only one providing significant results for both populations. Given the lack of consistency among the different tests, we recommend using multiple approaches to investigate possible past bottlenecks. The small effective population size (about 50) in the Iberian Peninsula compared to the presumed extant population size could indicate that the bottleneck was more powerful than initially suspected or an overestimation of the current population. The risks associated with small effective population sizes suggest that the genetic change in this population should be closely monitored in the future. On the other hand, the relatively small effective population size for Russian wolves (a few hundred individuals) could indicate some fragmentation, contrary to what is commonly assumed.     

Genome-wide patterns of nucleotide polymorphism in domesticated rice

Domesticated Asian rice (Oryza sativa) is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs) in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models to explain contemporary patterns of polymorphisms in rice, including a (i) selectively neutral population bottleneck model, (ii) bottleneck plus migration model, (iii) multiple selective sweeps model, and (iv) bottleneck plus selective sweeps model. We find that a simple bottleneck model, which has been the dominant demographic model for domesticated species, cannot explain the derived nucleotide polymorphism site frequency spectrum in rice. Instead, a bottleneck model that incorporates selective sweeps, or a more complex demographic model that includes subdivision and gene flow, are more plausible explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that selection results only in a local signature of variation.     

Evidence for a selective sweep in the wapl region of Drosophila melanogaster

A scan of the X chromosome of a European Drosophila melanogaster population revealed evidence for the recent action of positive directional selection at individual loci. In this study we analyze one such region that showed no polymorphism in the genome scan (located in cytological division 2C10-2E1). We detect a 60.5-kb stretch of DNA encompassing the genes ph-d, ph-p, CG3835, bcn92, Pgd, wapl, and Cyp4d1, which almost completely lacks variation in the European sample. Loci flanking this region show a skewed frequency spectrum at segregating sites, strong haplotype structure, and high levels of linkage disequilibrium. Neutrality tests reveal that these data are unlikely under both the neutral equilibrium model and the simple bottleneck scenarios. In contrast, newly developed maximum-likelihood ratio tests suggest that strong selection has acted recently on the region under investigation, causing a selective sweep. Evidence that this sweep may have originated in an ancestral population in Africa is presented.     

Inferring Weak Selection from Patterns of Polymorphism and Divergence at ``silent' Sites in Drosophila DNA

Patterns of codon usage and ``silent'''' DNA divergence suggest that natural selection discriminates among synonymous codons in Drosophila. ``Preferred'''' codons are consistently found in higher frequencies within their synonymous families in Drosophila melanogaster genes. This suggests a simple model of silent DNA evolution where natural selection favors mutations from unpreferred to preferred codons (preferred changes). Changes in the opposite direction, from preferred to unpreferred synonymous codons (unpreferred changes), are selected against. Here, selection on synonymous DNA mutations is investigated by comparing the evolutionary dynamics of these two categories of silent DNA changes. Sequences from outgroups are used to determine the direction of synonymous DNA changes within and between D. melanogaster and Drosophila simulans for five genes. Population genetics theory shows that differences in the fitness effect of mutations can be inferred from the comparison of ratios of polymorphism to divergence. Unpreferred changes show a significantly higher ratio of polymorphism to divergence than preferred changes in the D. simulans lineage, confirming the action of selection at silent sites. An excess of unpreferred fixations in 28 genes suggests a relaxation of selection on synonymous mutations in D. melanogaster. Estimates of selection coefficients for synonymous mutations (3.6 <|N(e)s| < 1.3) in D. simulans are consistent with the reduced efficacy of natural selection (|N(e)s| < 1) in the three- to sixfold smaller effective population size of D. melanogaster. Synonymous DNA changes appear to be a prevalent class of weakly selected mutations in Drosophila.     

Statistical Tests of Neutrality of Mutations against Population Growth, Hitchhiking and Background Selection

The main purpose of this article is to present several new statistical tests of neutrality of mutations against a class of alternative models, under which DNA polymorphisms tend to exhibit excesses of rare alleles or young mutations. Another purpose is to study the powers of existing and newly developed tests and to examine the detailed pattern of polymorphisms under population growth, genetic hitchhiking and background selection. It is found that the polymorphic patterns in a DNA sample under logistic population growth and genetic hitchhiking are very similar and that one of the newly developed tests, F(s), is considerably more powerful than existing tests for rejecting the hypothesis of neutrality of mutations. Background selection gives rise to quite different polymorphic patterns than does logistic population growth or genetic hitchhiking, although all of them show excesses of rare alleles or young mutations. We show that Fu and Li''s tests are among the most powerful tests against background selection. Implications of these results are discussed.     

Non-African origin of a local beneficial mutation in D. melanogaster

It is well understood that the out-of-Africa habitat expansion of D. melanogaster was associated with the fixation of many beneficial mutations. Nevertheless, it is not clear yet whether these beneficial mutations segregated already in Africa or originated outside of Africa. In this article, we describe an ongoing selective sweep specific to one European population. One microsatellite allele has increased in a population from The Netherlands to a frequency of 18%, whereas it is virtually absent in 12 other European populations. The selective sweep resulted in a genomic region of more than 600 kb that is identical by descent. This is probably the first evidence of a beneficial mutation that has arisen outside of Africa and has resulted in a selective sweep localized in a population from The Netherlands.