ORIGINAL INVESTIGATION Directional migration in the Hindu castes: inferences from mitochondrial, autosomal and Y-chromosomal data

Abstract Genetic, ethnographic, and historical evidence suggests that the Hindu castes have been highly endogamous for several thousand years and that, when movement between castes does occur, it typically consists of females joining castes of higher social status. However, little is known about migration rates in these populations or the extent to which migration occurs between caste groups of low, middle, and high social status. To investigate these aspects of migration, we analyzed the largest collection of genetic markers collected to date in Hindu caste populations. These data included 45 newly typed autosomal short tandem repeat polymorphisms (STRPs), 411 bp of mitochondrial DNA sequence, and 43 Y-chromosomal single-nucleotide polymorphisms that were assayed in more than 200 individuals of known caste status sampled in Andrah Pradesh, in South India. Application of recently developed likelihood-based analyses to this dataset enabled us to obtain genetically derived estimates of intercaste migration rates. STRPs indicated migration rates of 1-2% per generation between high-, middle-, and low-status caste groups. We also found support for the hypothesis that rates of gene flow differ between maternally and paternally inherited genes. Migration rates were substantially higher in maternally than in paternally inherited markers. In addition, while prevailing patterns of migration involved movement between castes of similar rank, paternally inherited markers in the low-status castes were most likely to move into high-status castes. Our findings support earlier evidence that the caste system has been a significant, longterm source of population structuring in South Indian Hindu populations, and that patterns of migration differ between males and females

Comparative genomics of primate CCL3L and CCL4L loci.

<p>(A) Comparison of <i>CCL3L</i> and <i>CCL4L</i> in human and nonhuman primates. The top panel shows a schema of the chemokine locus at human chromosome 17q12 based on the NT_010799.14 contig. <i>CCL3</i> and <i>CCL4</i> exist as single-copy genes per haploid genome. The genes encoding the non-allelic isoforms of <i>CCL3</i> (National Center for Biotechnology Information gene ID given in parentheses) are denoted as <i>CCL3L1</i> (6349), <i>CCL3L2</i> (390788), and <i>CCL3L3</i> (414062) and those of <i>CCL4</i> are denoted as <i>CCL4L1</i> (9560) and <i>CCL4L2</i> (388372). The middle panel shows a schema of the <i>CCL3L</i> and <i>CCL4L</i> locus in chimpanzee based on the chromosome 17NW_001226927.1 contig. <i>CCL3L</i> orthologs (denoted as “1” and “2”) map ∼ 1.6 Mb apart in this contig. In contrast to the human locus, chimpanzee contigs lack <i>CCL3L2</i>. The bottom panel shows a schema of the <i>CCL3L</i> and <i>CCL4L</i> locus in rhesus monkey based on chromosome 16 NW_001103987 contig. Of note, other orthologs of <i>CCL3L</i> and <i>CCL4L</i> were found in two other rhesus contigs (NW_001103644.1 and NW_001102959). CpG islands found in primate <i>CCL3L</i> and <i>CCL4L</i> loci are also depicted. Distances between genes are approximate, and the map is not to scale. The arrows denote the orientation of the genes. k, kb; M, Mb. (B and C) Schematic representation of genomic and mRNA structure of human <i>CCL3L</i> and <i>CCL4L</i> genes that have mRNA splicing patterns that are similar (B) or dissimilar (C) to <i>CCL3</i> and <i>CCL4.</i> Exons are represented as boxes and introns as connecting lines labeled with Roman numbers; the splicing pattern is denoted by the dashed lines. <i>CCL3L1</i>, <i>CCL3L3</i>, and <i>CCL4L2</i> are each composed of three exons, and the start codon (denoted with an arrow) is located in the first exon. <i>CCL4L1</i> has a transition in the splicing acceptor site located in intron II (AG→GG, indicated in red), which results in the generation of aberrantly spliced transcripts that use alternative acceptor sites located either in the intron II or in the third exon <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000359#pgen.1000359-Colobran1" target="_blank">[26]</a>. <i>CCL3L2</i> was previously considered as a pseudogene <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000359#pgen.1000359-Menten1" target="_blank">[5]</a>. However, recent studies in our lab suggest that it has a four exon structure and is predicted to transcribe alternatively spliced mRNA species with open reading frames (ORFs) that contain chemokine-like domains <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000359#pgen.1000359-ShostakovichKoretskaya1" target="_blank">[16]</a>; CCL3L2 mRNA transcripts originate from two novel upstream exons (designated as 1A and 1B) and are linked to the second and third exons, which are homologous to exons 2 and 3 found in <i>CCL3L1</i> or <i>CCL3L3</i>. (D) Nucleotide sequence of human <i>CCL3L1</i> (or <i>CCL3L3</i>) and its alignment with four distinct chimpanzee <i>CCL3L</i> (<i>chCCL3L</i>) orthologous genes from the translation initiation site until the start of intron 1. The translational start codon in <i>hCCL3L1</i> is underlined. Horizontal arrows delimit the exon–intron boundaries. Dashes indicate deletions. Polymorphic sites relative to the <i>hCCL3L1</i> are shown in red. The vertical arrow represents the site for signal peptidase cleavage. <i>chCCL3L ortholog 1</i> is predicted to encode a chemokine with amino acids that are shared with both hCCL3L1 and hCCL3. <i>chCCL3L ortholog 2</i> has a deletion of 17 nucleotides (relative to <i>hCCL3L1</i>) that may lead to loss of the signal peptide cleavage motif. Notably, two additional and different <i>CCL3L</i> orthologs were found in two independent chimpanzee contigs, denoted as NW_001227489.1 (ortholog 3) and NW_001227474.1 (ortholog 4), which have a mutation at the translation initiation site (shown in purple) and differ from each other in the splicing donor site of intron 1 (shown in blue) and other genomic regions (unpublished data). Of note, all four <i>chCCL3L1</i> orthologs had sequences that were completely homologous to the primer–probe sets used to detect <i>CCL3L</i> CNV in humans and chimpanzee previously <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000359#pgen.1000359-Gonzalez1" target="_blank">[12]</a> and by Degenhardt et al. <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000359#pgen.1000359-Degenhardt1" target="_blank">[9]</a>. All the chimpanzee orthologs are also predicted to encode transcripts with potential ORFs with chemokine-like domains. The accession numbers for the predicted ORFs encoded by chimpanzee <i>CCL3L</i> orthologs 1, 2, 3, and 4 are NP_001029254, XP_001152451, XP_001172388, and XP_001172226, respectively.</p

Mutations in Genes Encoding Fast-Twitch Contractile Proteins Cause Distal Arthrogryposis Syndromes

The distal arthrogryposes (DAs) are a group of disorders characterized by multiple congenital contractures of the limbs. We previously mapped a locus for DA type 2B (DA2B), the most common of the DAs, to chromosome 11. We now report that DA2B is caused by mutations in TNNI2 that are predicted to disrupt the carboxy-terminal domain of an isoform of troponin I (TnI) specific to the troponin-tropomyosin (Tc-Tm) complex of fast-twitch myofibers. Because the DAs are genetically heterogeneous, we sought additional candidate genes by examining modifiers of mutant Drosophila isoforms of TnI. One of these modifiers, Tm2, encodes tropomyosin, another component of the Tc-Tm complex. A human homologue of Tm2, TPM2, enocodes β-tropomyosin and maps to the critical interval of DA type 1 (DA1). We discovered that DA1 is caused by substitution of a highly conserved amino acid residue in β-tropomyosin. These findings suggest that DAs, in general, may be caused by mutations in genes encoding proteins of the contractile apparatus specific to fast-twitch myofibers. This provides a new opportunity to directly study the etiology and pathogenesis of multiple-congenital-contracture syndromes