(1/112) Maximum-likelihood estimation of migration rates and effective population numbers in two populations using a coalescent approach.

A new method for the estimation of migration rates and effective population sizes is described. It uses a maximum-likelihood framework based on coalescence theory. The parameters are estimated by Metropolis-Hastings importance sampling. In a two-population model this method estimates four parameters: the effective population size and the immigration rate for each population relative to the mutation rate. Summarizing over loci can be done by assuming either that the mutation rate is the same for all loci or that the mutation rates are gamma distributed among loci but the same for all sites of a locus. The estimates are as good as or better than those from an optimized FST-based measure. The program is available on the World Wide Web at http://evolution.genetics. washington.edu/lamarc.html/.  (+info)

(2/112) Gene genealogies in geographically structured populations.

Population genetics theory has dealt only with the spatial or geographic pattern of degrees of relatedness or genetic similarity separately for each point in time. However, a frequent goal of experimental studies is to infer migration patterns that occurred in the past or over extended periods of time. To fully understand how a present geographic pattern of genetic variation reflects one in the past, it is necessary to build genealogy models that directly relate the two. For the first time, space-time probabilities of identity by descent and coalescence probabilities are formulated and characterized in this article. Formulations for general migration processes are developed and applied to specific types of systems. The results can be used to determine the level of certainty that genes found in present populations are descended from ancient genes in the same population or nearby populations vs. geographically distant populations. Some parameter combinations result in past populations that are quite distant geographically being essentially as likely to contain ancestors of genes at a given population as the past population located at the same place. This has implications for the geographic point of origin of ancestral, "Eve," genes. The results also form the first model for emerging "space-time" molecular genetic data.  (+info)

(3/112) Spatial and temporal distribution of the neutral polymorphisms in the last ZFX intron: analysis of the haplotype structure and genealogy.

With 10 segregating sites (simple nucleotide polymorphisms) in the last intron (1089 bp) of the ZFX gene we have observed 11 haplotypes in 336 chromosomes representing a worldwide array of 15 human populations. Two haplotypes representing 77% of all chromosomes were distributed almost evenly among four continents. Five of the remaining haplotypes were detected in Africa and 4 others were restricted to Eurasia and the Americas. Using the information about the ancestral state of the segregating positions (inferred from human-great ape comparisons), we applied coalescent analysis to estimate the age of the polymorphisms and the resulting haplotypes. The oldest haplotype, with the ancestral alleles at all the sites, was observed at low frequency only in two groups of African origin. Its estimated age of 740 to 1100 kyr corresponded to the time to the most recent common ancestor. The two most frequent worldwide distributed haplotypes were estimated at 550 to 840 and 260 to 400 kyr, respectively, while the age of the continentally restricted polymorphisms was 120 to 180 kyr and smaller. Comparison of spatial and temporal distribution of the ZFX haplotypes suggests that modern humans diverged from the common ancestral stock in the Middle Paleolithic era. Subsequent range expansion prevented substantial gene flow among continents, separating African groups from populations that colonized Eurasia and the New World.  (+info)

(4/112) A predominantly indigenous paternal heritage for the Austronesian-speaking peoples of insular Southeast Asia and Oceania.

Modern humans reached Southeast Asia and Oceania in one of the first dispersals out of Africa. The resulting temporal overlap of modern and archaic humans-and the apparent morphological continuity between them-has led to claims of gene flow between Homo sapiens and H. erectus. Much more recently, an agricultural technology from mainland Asia spread into the region, possibly in association with Austronesian languages. Using detailed genealogical study of Y chromosome variation, we show that the majority of current Austronesian speakers trace their paternal heritage to Pleistocene settlers in the region, as opposed to more-recent agricultural immigrants. A fraction of the paternal heritage, however, appears to be associated with more-recent immigrants from northern populations. We also show that the northern Neolithic component is very unevenly dispersed through the region, with a higher contribution in Southeast Asia and a nearly complete absence in Melanesia. Contrary to claims of gene flow (under regional continuity) between H. erectus and H. sapiens, we found no ancestral Y chromosome lineages in a set of 1,209 samples. The finding excludes the possibility that early hominids contributed significantly to the paternal heritage of the region.  (+info)

(5/112) Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa.

Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12-31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.  (+info)

(6/112) Genetic factors contribute to the risk of developing endometriosis.

BACKGROUND: Endometriosis is known to cluster within nuclear families. The extent of familial clustering can be evaluated in Iceland with its large population-based genealogical database. METHODS AND RESULTS: Applying several measures of familiality we demonstrated that 750 women with endometriosis were significantly more interrelated than matched control groups. The risk ratio for sisters was 5.20 (P < 0.001) and for cousins 1.56 (P = 0.003). The average kinship coefficient for the patients was significantly higher than that calculated for 1000 sets of 750 matched controls (P < 0.001) and this remained significant when contribution from first-degree relatives was excluded (P < 0.05). The minimum number of ancestors required to account for the group of patients was compared with the minimum number of ancestors required to account for the control groups at different time points in the past. The minimum number of founders for the group of patients was significantly smaller than for the control groups. Affected cousin pairs were as likely to be paternally connected as maternally connected. CONCLUSIONS: This is the first population-based study using an extensive genealogy database to examine the genetic contribution to endometriosis. A genetic factor is present, with a raised risk in close and more distant relatives, and a definite kinship factor with maternal and paternal inheritance contributing.  (+info)

(7/112) Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data.

Molecular sequences obtained at different sampling times from populations of rapidly evolving pathogens and from ancient subfossil and fossil sources are increasingly available with modern sequencing technology. Here, we present a Bayesian statistical inference approach to the joint estimation of mutation rate and population size that incorporates the uncertainty in the genealogy of such temporally spaced sequences by using Markov chain Monte Carlo (MCMC) integration. The Kingman coalescent model is used to describe the time structure of the ancestral tree. We recover information about the unknown true ancestral coalescent tree, population size, and the overall mutation rate from temporally spaced data, that is, from nucleotide sequences gathered at different times, from different individuals, in an evolving haploid population. We briefly discuss the methodological implications and show what can be inferred, in various practically relevant states of prior knowledge. We develop extensions for exponentially growing population size and joint estimation of substitution model parameters. We illustrate some of the important features of this approach on a genealogy of HIV-1 envelope (env) partial sequences.  (+info)

(8/112) Genealogy profiling through strain improvement by using metabolic network analysis: metabolic flux genealogy of several generations of lysine-producing corynebacteria.

A comprehensive approach of metabolite balancing, (13)C tracer studies, gas chromatography-mass spectrometry, matrix-assisted laser desorption ionization-time of flight mass spectrometry, and isotopomer modeling was applied for comparative metabolic network analysis of a genealogy of five successive generations of lysine-producing Corynebacterium glutamicum. The five strains examined (C. glutamicum ATCC 13032, 13287, 21253, 21526, and 21543) were previously obtained by random mutagenesis and selection. Throughout the genealogy, the lysine yield in batch cultures increased markedly from 1.2 to 24.9% relative to the glucose uptake flux. Strain optimization was accompanied by significant changes in intracellular flux distributions. The relative pentose phosphate pathway (PPP) flux successively increased, clearly corresponding to the product yield. Moreover, the anaplerotic net flux increased almost twofold as a consequence of concerted regulation of C(3) carboxylation and C(4) decarboxylation fluxes to cover the increased demand for lysine formation; thus, the overall increase was a consequence of concerted regulation of C(3) carboxylation and C(4) decarboxylation fluxes. The relative flux through isocitrate dehydrogenase dropped from 82.7% in the wild type to 59.9% in the lysine-producing mutants. In contrast to the NADPH demand, which increased from 109 to 172% due to the increasing lysine yield, the overall NADPH supply remained constant between 185 and 196%, resulting in a decrease in the apparent NADPH excess through strain optimization. Extrapolated to industrial lysine producers, the NADPH supply might become a limiting factor. The relative contributions of PPP and the tricarboxylic acid cycle to NADPH generation changed markedly, indicating that C. glutamicum is able to maintain a constant supply of NADPH under completely different flux conditions. Statistical analysis by a Monte Carlo approach revealed high precision for the estimated fluxes, underlining the fact that the observed differences were clearly strain specific.  (+info)