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Genomics in the Journals: 2014.01.09

NEW YORK (GenomeWeb News) – In Cell, researchers from China and the US described an approach for analyzing the genomes of individual human oocytes — a strategy that's expected to prove useful for understanding the process of meiotic cell division and for improving the efficiency of in vitro fertilization.

Using this scheme — which centers on sequencing in conjunction with "multiple amplification cycle (MALBAC) — the team demonstrated that it was possible to find SNPs and phase the genomes of polar bodies and oocyte pronuclei that had been provided by egg donors.

Based on their findings so far, the investigators are optimistic that the strategy may provide insights into the presence or absence of disease-related variants in oocytes prior to fertilization and implantation. They noted that the method can also unearth aneuploidy events, including those jeopardizing the likelihood of live births.

"The MALBAC-based pre-implantation genomic screening in in vitro fertilization enables accurate and cost-effective selection of normal fertilized eggs for embryo transfer," senior authors Fuchou Tang, Sunney Xie, and Jie Qiao, researchers affiliated with Peking University and other centers, and their colleagues, wrote.

An international team led by investigators in the Netherlands, Spain, and the UK has identified new loci linked to the autoimmune condition systemic sclerosis, also known as scleroderma, by focusing on parts of the genome implicated in other autoimmune disease-related processes.

As they reported in the American Journal of Human Genetics, the researchers used the custom, high-density Immunochip array to genotype 1,833 US or Spanish individuals of European ancestry with systemic sclerosis and nearly 3,500 unaffected controls from the same population.

A comparison of variant profiles in these cases and controls, coupled with imputation, helped the team pin down SNP and predicted amino acid variants within a human leukocyte antigen region coinciding with systemic sclerosis risk. That association appeared to stem from seven SNPs and half a dozen predicted amino acid polymorphisms in the HLA area.

The investigators saw some potential risk factors for systemic sclerosis outside of the HLA region, too. By folding in information for another 4,017 cases and 5,935 controls, they found known risk loci and detected new associations between systemic scleroderma risk and three loci on chromosomes 3 and 6. That analysis also revealed shakier ties between the autoimmune condition and a fourth region on chromosome 11.

"Our study has increased the number of known genetic associations with [systemic sclerosis], provided further insights into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci," the study's authors wrote.

Researchers from Finland, Sweden, and China delved into the basis of a known association between a non-protein-coding chromosome 6 variant and increased risk of prostate cancer — work that they presented in Nature Genetics.

With the help of HOXB13-targeted chromatin immunoprecipitation sequencing experiments in prostate cancer cells, the team determined that the SNP in question, known as rs339331, falls in a portion of chromosome 6 that is bound by the transcription factor encoded by HOXB13.

And through a series of follow-up experiments, the investigators teased apart additional details of this effect, showing that the risky version of rs339331 prompts the activation of a HOXB13-controled transcriptional enhancer.

That, in turn, spurs higher-than-usual expression of the transcription factor gene RFX6, they reported, apparently prompting prostate cell migration and proliferation. In contrast, those processes were dampened in prostate cancer cells in which RFX6 expression was curbed experimentally.

McMaster University's Hendrik Poinar and colleagues published a brief report in the New England Journal of Medicine characterizing the genome of a cholera-causing Vibrio cholerae strain involved in an outbreak in Philadelphia in 1849.

The researchers applied targeted enrichment and high-throughput Illumina sequencing to bits of the bacterial pathogen's DNA that had been coaxed from the preserved museum sample of intestinal tissue from an 1849 cholera victim in Philadelphia. In the process, they produced a draft version of the V. cholerae genome covered to an average depth of 15 fold.

Results of their analyses indicated that the waterborne bug behind the 19th century outbreak in Philadelphia likely belonged to a version of the "classical" O1 biotype that's between 95 percent and 97 percent similar to another classical V. cholerae strain, O395. They found differences at just over 200 SNPs and a few toxin prophage sequence sites between O395 and Philadelphia outbreak strain, with the latter lacking three genomic islands present in O395.

Together, such patterns provide clues about relationships between the classical V. cholerae strains — which appear to have been involved in outbreaks prior to the 20th century — and the "El Tor" strain that has been linked to the cholera outbreak in 2010 in Haiti following that country's earthquake as well as other recent outbreaks.

Further studies of other historical strains may help in further fleshing out that picture, the study's authors noted, and in understanding the pathogens' virulence profiles.

"The genomes of ancestral pathogens that have descendants today reside in these archival medical collections all over the world," Poinar said in a statement. "We have access to hundreds of thousands of ancient specimens, which hold tremendous potential to determine the origins of past epidemics."

In the American Journal of Human Genetics, researchers from the Wellcome Trust Sanger Institute and elsewhere reported that they were unable to uncover any genetic evidence upholding the so-called thrifty gene hypothesis. That hypothesis posits that genetic regions linked to type 2 diabetes risk were of some benefit to people earlier in evolutionary history.

Drawing on a cohort of samples from people of African, European, and East Asian ancestry, the team scoured 65 loci linked to T2D susceptibility through previous genome-wide association studies for signs of positive selection. In a collective analysis, Xue and colleagues found no signal of enrichment of positive selections. Then by examining the loci individually, they noted evidence of positive selection at some 14 loci. However, both risk and protective alleles were similarly favored.

"We found evidence for positive selection in only a few of the 65 variants, and selection favored the protective and risk alleles for type 2 diabetes in similar proportions," said first author Qasim Ayub from the Wellcome Trust in a statement. "This is no more than what we would expect to find for a random set of genomic variants."

The team added that it "is more likely that T2D risk variants have been, for most of human evolutionary history, effectively neutral."