Cone-Rod Dystrophy Due to Mutations in a Novel Photoreceptor-Specific Homeobox Gene (CRX) Essential for Maintenance of the Photoreceptor

Genes associated with inherited retinal degeneration have been found to encode proteins required for phototransduction, metabolism, or structural support of photoreceptors. Here we show that mutations in a novel photoreceptor-specific homeodomain transcription factor gene (CRX) cause an autosomal dominant form of cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13. In affected members of a CORD2-linked family, the highly conserved glutamic acid at the first position of the recognition helix is replaced by alanine (E80A). In another CRD family, a 1 bp deletion (E168 [delta1 bp]) within a novel sequence, the WSP motif, predicts truncation of the C-terminal 132 residues of CRX. Mutations in the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative effect and demonstrate that CRX is essential for the maintenance of mammalian photoreceptorsThis work was supported by the RP Foundation of Canada (R. R. M.), the Foundation Fighting Blindness (R. R. M. and S. G. J.), the Canadian Genetic Disease Network (R. R. M. and A. D.), the Medical Research Council of Canada (R. R. M.), The Wellcome Trust (043825/Z/95) and the Human Genome Mapping Resource Centre (C. Y. G.-E. and S. S. B.), the Howard Hughes Medical Institute and NIH R01 EY0 8064 (C. L. C.), the Canadian Genome Analysis and Technology Genome Resource Facility (S. W. S. and L.-C. T.), the NIH/NEI (EY05627) (S. G. J.), and the Greek National Scholarship Foundation (M. P.). R. R. M. and L.-C. T. are International Research Scholars of the Howard Hughes Medical Institute

The Y-Chromosome Tree Bursts into Leaf: 13,000 High-Confidence SNPs Covering the Majority of Known Clades

Many studies of human populations have used the male-specific region of the Y chromosome (MSY) as a marker, but MSY sequence variants have traditionally been subject to ascertainment bias. Also, dating of haplogroups has relied on Y-specific short tandem repeats (STRs), involving problems of mutation rate choice, and possible long-term mutation saturation. Next-generation sequencing can ascertain single nucleotide polymorphisms (SNPs) in an unbiased way, leading to phylogenies in which branch-lengths are proportional to time, and allowing the times-to-most-recent-common-ancestor (TMRCAs) of nodes to be estimated directly. Here we describe the sequencing of 3.7 Mb of MSY in each of 448 human males at a mean coverage of 51x, yielding 13,261 high-confidence SNPs, 65.9% of which are previously unreported. The resulting phylogeny covers the majority of the known clades, provides date estimates of nodes, and constitutes a robust evolutionary framework for analyzing the history of other classes of mutation. Different clades within the tree show subtle but significant differences in branch lengths to the root. We also apply a set of 23 Y-STRs to the same samples, allowing SNP- and STR-based diversity and TMRCA estimates to be systematically compared. Ongoing purifying selection is suggested by our analysis of the phylogenetic distribution of nonsynonymous variants in 15 MSY single-copy genes

Large-scale recent expansion of European patrilineages shown by population resequencing

The proportion of Europeans descending from Neolithic farmers similar to 10 thousand years ago (KYA) or Palaeolithic hunter-gatherers has been much debated. The male-specific region of the Ychromosome (MSY) has been widely applied to this question, but unbiased estimates of diversity and time depth have been lacking. Here we show that European patrilineages underwent a recent continent-wide expansion. Resequencing of 3.7Mb of MSY DNA in 334 males, comprising 17 European and Middle Eastern populations, defines a phylogeny containing 5,996 single-nucleotide polymorphisms. Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of our sample, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. A continuous swathe of 13/17 populations share similar histories featuring a demographic expansion starting similar to 2.1-4.2 KYA. Our results are compatible with ancient MSY DNA data, and contrast with data on mitochondrial DNA, indicating a widespread male-specific phenomenon that focuses interest on the social structure of Bronze Age Europe.Peer reviewe

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

Fst analysis in the main geographic regions.

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

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

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