Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

Background: Genetic variation at NAT2 has been long recognized as the cause of differential ability to metabolize a wide variety of drugs of therapeutic use. Here, we explore the pattern of genetic variation in 12 human populations that significantly extend the geographic range and resolution of previous surveys, to test the hypothesis that different dietary regimens and lifestyles may explain inter-population differences in NAT2 variation. Methodology/Principal Findings: The entire coding region was resequenced in 98 subjects and six polymorphic positions were genotyped in 150 additional subjects. A single previously undescribed variant was found (34T>C; 12Y>H). Several aspects of the data do not fit the expectations of a neutral model, as assessed by coalescent simulations. Tajima's D is positive in all populations, indicating an excess of intermediate alleles. The level of between-population differentiation is low, and is mainly accounted for by the proportion of fast vs. slow acetylators. However, haplotype frequencies significantly differ across groups of populations with different subsistence. Conclusions/Significance: Data on the structure of haplotypes and their frequencies are compatible with a model in which slow-causing variants were present in widely dispersed populations before major shifts to pastoralism and/or agriculture. In this model, slow-causing mutations gained a selective advantage in populations shifting from hunting-gathering to pastoralism/agriculture. We suggest the diminished dietary availability of folates resulting from the nutritional shift, as the possible cause of the fitness increase associated to haplotypes carrying mutations that reduce enzymatic activity. © 2008 Luca et al

Origin and spread of human mitochondrial DNA haplogroup U7

Human mitochondrial DNA haplogroup U is among the initial maternal founders in Southwest Asia and Europe and one that best indicates matrilineal genetic continuity between late Pleistocene hunter-gatherer groups and present-day populations of Europe. While most haplogroup U subclades are older than 30 thousand years, the comparatively recent coalescence time of the extant variation of haplogroup U7 (~16–19 thousand years ago) suggests that its current distribution is the consequence of more recent dispersal events, despite its wide geographical range across Europe, the Near East and South Asia. Here we report 267 new U7 mitogenomes that – analysed alongside 100 published ones – enable us to discern at least two distinct temporal phases of dispersal, both of which most likely emanated from the Near East. The earlier one began prior to the Holocene (~11.5 thousand years ago) towards South Asia, while the later dispersal took place more recently towards Mediterranean Europe during the Neolithic (~8 thousand years ago). These findings imply that the carriers of haplogroup U7 spread to South Asia and Europe before the suggested Bronze Age expansion of Indo-European languages from the Pontic-Caspian Steppe region

Enlarging the gene-geography of Europe and the Mediterranean area to STR loci of common forensic use: longitudinal and latitudinal frequency gradients

Background: Tetranucleotide Short Tandem Repeats (STRs) for human identification and common use in forensic cases have recently been used to address the population genetics of the North-Eastern Mediterranean area. However, to gain confidence in the inferences made using STRs, this kind of analysis should be challenged with changes in three main aspects of the data, i.e. the sizes of the samples, their distance across space and the genetic background from which they are drawn.Aim: To test the resilience of the gradients previously detected in the North-Eastern Mediterranean to the enlargement of the surveyed area and population set, using revised data.Subjects and methods: STR genotype profiles were obtained from a publicly available database (PopAffilietor databank) and a dataset was assembled including >7000 subjects from the Arabian Peninsula to Scandinavia, genotyped at eight loci. Spatial principal component analysis (sPCA) was applied and the frequency maps of the nine alleles which contributed most strongly to sPC1 were examined in detail.Results: By far the greatest part of diversity was summarised by a single spatial principal component (sPC1), oriented along a SouthEast-to-NorthWest axis. The alleles with the top 5% squared loadings were TH01(9.3), D19S433(14), TH01(6), D19S433(15.2), FGA(20), FGA(24), D3S1358(14), FGA(21) and D2S1338(19). These results confirm a clinal pattern over the whole range for at least four loci (TH01, D19S433, FGA, D3S1358).Conclusions: Four of the eight STR loci (or even alleles) considered here can reproducibly capture continental arrangements of diversity. This would, in principle, allow for the exploitation of forensic data to clarify important aspects in the formation of local gene pools.Italian Ministry of Justice [CUP E81J10001270005

A finely resolved phylogeny of Y chromosome Hg J illuminates the processes of Phoenician and Greek colonizations in the Mediterranean

In order to improve the phylogeography of the male-specific genetic traces of Greek and Phoenician colonizations on the Northern coasts of the Mediterranean, we performed a geographically structured sampling of seven subclades of haplogroup J in Turkey, Greece and Italy. We resequenced 4.4 Mb of Y-chromosome in 58 subjects, obtaining 1079 high quality variants. We did not find a preferential coalescence of Turkish samples to ancestral nodes, contradicting the simplistic idea of a dispersal and radiation of Hg J as a whole from the Middle East. Upon calibration with an ancient Hg J chromosome, we confirmed that signs of Holocenic Hg J radiations are subtle and date mainly to the Bronze Age. We pinpointed seven variants which could potentially unveil star clusters of sequences, indicative of local expansions. By directly genotyping these variants in Hg J carriers and complementing with published resequenced chromosomes (893 subjects), we provide strong temporal and distributional evidence for markers of the Greek settlement of Magna Graecia (J2a-L397) and Phoenician migrations (rs760148062). Our work generated a minimal but robust list of evolutionarily stable markers to elucidate the demographic dynamics and spatial domains of male-mediated movements across and around the Mediterranean, in the last 6,000 years

Representation of effective migration surfaces as obtained with EEMS on the reduced datasets derived from sPC 1 (A) and sPC2 (B).

<p>The coloured area covers only the user-defined polygon. The grid used by the program is shown in grey. Note that only 34 sampled demes appear (black dots, with size proportional to the n. of individuals), assigned to a grid vertex and not necessarily coinciding exactly with the original sampling location. Pooled locations were (numbered as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0167065#pone.0167065.s011" target="_blank">S1 Table</a>): 6+7, 9+10, 13+14+15+16, 25+26, 30+32. Note the different colour scales between the two maps. In both maps brown belts correspond to low migration values, i.e. barriers to gene flow.</p

Fst analysis in the main geographic regions.

<p>Fst analysis in the main geographic regions.</p

Maps of: A) scores for the 41 locations in sPC1 obtained on the full dataset with adegenet; B) scores in sPC2 obtained as in A; C) posterior assignment probabilities of the 41 locations to either of two clusters obtained on the reduced dataset derived from sPC1 with Geneland; D) posterior assignment probabilities of the 41 locations to either of two clusters obtained on the reduced dataset derived from sPC2 with Geneland.

<p>In A and B white and black squares represent negative and positive scores, respectively, with square size proportional to the absolute value (inset in panel A). In each of panels C and D shades of grey indicate probabilities of assignment to one of two mutually exclusive clusters from 0 (dark grey) to 1 (white). Color versions of panels C and D are reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0167065#pone.0167065.s007" target="_blank">S7 Fig</a>.</p

Loci and alleles with the strongest impact on the SpatialPCA eigenvalues 1 and 2.

<p>Loci and alleles with the strongest impact on the SpatialPCA eigenvalues 1 and 2.</p