Whole genome sequencing and microsatellite analysis of the Plasmodium falciparum E5 NF54 strain show that the var, rifin and stevor gene families follow Mendelian inheritance

Background: Plasmodium falciparum exhibits a high degree of inter-isolate genetic diversity in its variant surface antigen (VSA) families: P. falciparum erythrocyte membrane protein 1, repetitive interspersed family (RIFIN) and subtelomeric variable open reading frame (STEVOR). The role of recombination for the generation of this diversity is a subject of ongoing research. Here the genome of E5, a sibling of the 3D7 genome strain is presented. Short and long read whole genome sequencing (WGS) techniques (Ilumina, Pacific Bioscience) and a set of 84 microsatellites (MS) were employed to characterize the 3D7 and non-3D7 parts of the E5 genome. This is the first time that VSA genes in sibling parasites were analysed with long read sequencing technology. Results: Of the 5733 E5 genes only 278 genes, mostly var and rifin/stevor genes, had no orthologues in the 3D7 genome. WGS and MS analysis revealed that chromosomal crossovers occurred at a rate of 0–3 per chromosome. var, stevor and rifin genes were inherited within the respective non-3D7 or 3D7 chromosomal context. 54 of the 84 MS PCR fragments correctly identified the respective MS as 3D7- or non-3D7 and this correlated with var and rifin/stevor gene inheritance in the adjacent chromosomal regions. E5 had 61 var and 189 rifin/stevor genes. One large non-chromosomal recombination event resulted in a new var gene on chromosome 14. The remainder of the E5 3D7-type subtelomeric and central regions were identical to 3D7. Conclusions: The data show that the rifin/stevor and var gene families represent the most diverse compartments of the P. falciparum genome but that the majority of var genes are inherited without alterations within their respective parental chromosomal context. Furthermore, MS genotyping with 54 MS can successfully distinguish between two sibling progeny of a natural P. falciparum cross and thus can be used to investigate identity by descent in field isolates

Balancing selection is common in the extended MHC region but most alleles with opposite risk profile for autoimmune diseases are neutrally evolving

<p>Abstract</p> <p>Background</p> <p>Several susceptibility genetic variants for autoimmune diseases have been identified. A subset of these polymorphisms displays an opposite risk profile in different autoimmune conditions. This observation open interesting questions on the evolutionary forces shaping the frequency of these alleles in human populations.</p> <p>We aimed at testing the hypothesis whereby balancing selection has shaped the frequency of opposite risk alleles.</p> <p>Results</p> <p>Since balancing selection signatures are expected to extend over short genomic portions, we focused our analyses on 11 regions carrying putative functional polymorphisms that may represent the disease variants (and the selection targets). No exceptional nucleotide diversity was observed for <it>ZSCAN23</it>, <it>HLA-DMB</it>, <it>VARS2</it>, <it>PTPN22</it>, <it>BAT3</it>, <it>C6orf47</it>, and <it>IL10</it>; summary statistics were consistent with evolutionary neutrality for these gene regions. Conversely, <it>CDSN/PSORS1C1</it>, <it>TRIM10/TRIM40</it>, <it>BTNL2</it>, and <it>TAP2 </it>showed extremely high nucleotide diversity and most tests rejected neutrality, suggesting the action of balancing selection. For <it>TAP2 </it>and <it>BTNL2 </it>these signatures are not secondary to linkage disequilibrium with HLA class II genes. Nonetheless, with the exception of variants in <it>TRIM40 </it>and <it>CDSN</it>, our data suggest that opposite risk SNPs are not selection targets but rather have accumulated as neutral variants.</p> <p>Conclusion</p> <p>Data herein indicate that balancing selection is common within the extended MHC region and involves several non-HLA loci. Yet, the evolutionary history of most SNPs with an opposite effect for autoimmune diseases is consistent with evolutionary neutrality. We suggest that variants with an opposite effect on autoimmune diseases should not be considered a distinct class of disease alleles from the evolutionary perspective and, in a few cases, the opposite effect on distinct diseases may derive from complex haplotype structures in regions with high genetic diversity.</p

Fine-scale analysis of mechanisms and controlling factors in a meiotic recombination hotspot in dogs (canis familiaris)

Meiotic recombination re-shuffles genomes from one generation to the next. In humans and most other mammals, meiotic recombination events are clustered in 1-2 kb wide recombination hotspots, whose locations are determined in trans by the protein PR-domain containing 9 (PRDM9). Mice lacking PRDM9 direct recombination to promoters and functional elements, resulting in meiotic defects. Dogs (Canis familiaris) lack a functional copy of PRDM9, yet linkage data showed that historical recombination events cluster in functional elements, suggesting that there may be a mechanism enabling controlled recombination at these locations, and in the absence of PRDM9. However nothing is known about the de-novo activity of dog recombination hotspots and the patters of recombination resolution in this PRDM9 deficient species. I investigated a dog recombination hotspot for de-novo recombination events using pooled sperm typing, and uncovered high crossover frequencies affecting up to 1 % of sperm. Frequencies can differ by one order of magnitude between dogs. Fine-scale analysis of crossover-breakpoints revealed wide distributions of breaks across up to 10 kb within the hotspot region. I further detect asymmetric breakpoint distributions between crossover orientations and crossover-associated transmission distortion, suggesting biased recombination-initiation or -repair. This work is an elaborate fine-scale dissection of a mammalian PRDM9-independent active recombination hotspot

Studies at the hemochromatosis (HFE) locus : gene conversions, haplotypes, and association analysis

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2006.Includes bibliographical references.Haplotype-based association studies offer an exciting potential methodology for the identification of genes that contribute to complex traits. There is thus great interest in understanding the biological forces that shape haplotypes. We have studied a well-characterized genetic locus surrounding the gene responsible for hereditary hemochromatosis (HFE) to investigate the impact of meiotic recombination events upon haplotype structure in this region. First we identified crossover hotspots in order to define the boundaries of haplotype blocks in this locus. We then found that gene conversion events play a significant role in shaping haplotype structure within these haplotype blocks. These gene conversion events were not limited to recombination hotspots and occurred with a frequency as high as 1 in 104 per site per generation. Gene conversions lead to the creation of new haplotypes and we suggest that they are important for the spread of disease alleles in a population. In addition, we discuss how these events can be used as important tools in haplotype-based association studies. We also present an association study in a large Venezuelan cohort to search for genes that contribute to residual age of onset in Huntington's disease. We demonstrate significant association between multiple alleles in a region on chromosome 6p21.3.(cont.) We identify two candidate genes in this region, HFE and histone Hlt and demonstrate significant association of this region with age of onset in a male-specific model.by Junne Kamihara-Ting.Ph.D

A supergene determines highly divergent male reproductive morphs in the ruff

Three strikingly different alternative male mating morphs (aggressive 'independents', semicooperative 'satellites' and female-mimic 'faeders') coexist as a balanced polymorphism in the ruff, Philomachus pugnax, a lek-breeding wading bird1, 2, 3. Major differences in body size, ornamentation, and aggressive and mating behaviors are inherited as an autosomal polymorphism4, 5. We show that development into satellites and faeders is determined by a supergene6, 7, 8 consisting of divergent alternative, dominant and non-recombining haplotypes of an inversion on chromosome 11, which contains 125 predicted genes. Independents are homozygous for the ancestral sequence. One breakpoint of the inversion disrupts the essential CENP-N gene (encoding centromere protein N), and pedigree analysis confirms the lethality of homozygosity for the inversion. We describe new differences in behavior, testis size and steroid metabolism among morphs and identify polymorphic genes within the inversion that are likely to contribute to the differences among morphs in reproductive traits

Ancestral Hybridization Facilitated Species Diversification in the Lake Malawi Cichlid Fish Adaptive Radiation.

The adaptive radiation of cichlid fishes in East African Lake Malawi encompasses over 500 species that are believed to have evolved within the last 800,000 years from a common founder population. It has been proposed that hybridization between ancestral lineages can provide the genetic raw material to fuel such exceptionally high diversification rates, and evidence for this has recently been presented for the Lake Victoria region cichlid superflock. Here, we report that Lake Malawi cichlid genomes also show evidence of hybridization between two lineages that split 3-4 Ma, today represented by Lake Victoria cichlids and the riverine Astatotilapia sp. "ruaha blue." The two ancestries in Malawi cichlid genomes are present in large blocks of several kilobases, but there is little variation in this pattern between Malawi cichlid species, suggesting that the large-scale mosaic structure of the genomes was largely established prior to the radiation. Nevertheless, tens of thousands of polymorphic variants apparently derived from the hybridization are interspersed in the genomes. These loci show a striking excess of differentiation across ecological subgroups in the Lake Malawi cichlid assemblage, and parental alleles sort differentially into benthic and pelagic Malawi cichlid lineages, consistent with strong differential selection on these loci during species divergence. Furthermore, these loci are enriched for genes involved in immune response and vision, including opsin genes previously identified as important for speciation. Our results reinforce the role of ancestral hybridization in explosive diversification by demonstrating its significance in one of the largest recent vertebrate adaptive radiations.We acknowledge funding from Wellcome Trust grants WT206194 and WT207492 (H.S. and R.D.), the European Research Council, ERC CoG “CICHLID~X” (617585) and Swiss National Science Foundation, grant nr. 176039 (W.S) and the Royal Society – Leverhulme Trust Africa Awards AA100023 and AA130107 to MJG, BPN and GFT