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Genomics In The Journals: May 3, 2012

NEW YORK (GenomeWeb News) – In BMC Genetics, researchers from the National Institute of Deafness and Other Communication Disorders describe the approach that they used to find two quantitative trait loci involved in a form of high frequency hearing loss called presbycusis in a mouse model.

By crossing a high-frequency hearing loss strain with three other inbred mouse strains and doing genome-wide linkage analyses on mice descended from these crosses, the team tracked down a chromosome 7 QTL dubbed Hfhl1 and another QTL called Hfhl3 on chromosome 9. Each of these sites seems to influence hearing loss in a different frequency range, study authors noted, explaining that more work is needed to find other genetic features involved in the process.

"The high-frequency hearing loss loci, Hfhl1 and Hfhl3, explain only a portion of the variation in high-frequency hearing loss observed in these mice," NIDOCD researcher James Keller, the study's corresponding author, said in a statement. "Other loci, and cross talk between genes at different loci, probably account for much of the remainder — in fact we detected a number of additional loci that could account for some of the residual variation."

A UK-led team used insertional mutagenesis in mice to find a tumor suppressor gene that appears to influence pancreatic cancer development and progression.

Researchers used the Sleeping Beauty transposon to introduce additional genetic alterations in a mouse model carrying known pancreatic cancer-predisposing mutations, looking for genes that sped up cancer development. As they report in Nature, the screen led to genes with known roles in pancreatic ductal adenocarcinoma. But it also unearthed new candidate genes, including the deubiquitinase-coding gene USP9X, which contained inactivating mutations in more than half of the mouse tumors.

In pancreatic ductal adenocarcinoma patient cohorts from Australia, the US, and Germany, meanwhile, muted USP9X gene or protein expression coincided with poor outcomes and cancer metastasis, the study's authors noted, prompting them to argue that USP9X "is a major tumor suppressor gene with prognostic and therapeutic relevance in [pancreatic ductal adenocarcinoma]."

Two studies in Cell look at the role that SRGAP2 gene duplications have had in human brain evolution. Through a set of sequencing, copy number, and other analyses of the SRGAP2 genes, a University of Washington-led group concluded that SRGAP2, a gene involved in development of the brain's cortex, has undergone partial duplication at least three times in the human lineage — around 3.4 million, 2.4 million, and 1 million years ago — producing versions of the gene that are functionally antagonistic to the original gene.

"These episodic and large duplication events could have allowed for radical — potentially earth-shattering — changes in brain development and brain function," University of Washington genome sciences researcher Evan Eichler, the study's senior author, said in a statement.

Researchers from the US, Belgium, and China take a closer look at the functional role of SRGAP2 and its paralogs in a second Cell study. From gene expression and other studies in mouse and human neurons, that group concluded that the human-specific SRGAP2 duplications have produced versions of the gene that inhibit the function of the original gene, influencing the properties of neurons in the neurocortex and their connections with one another.

By sequencing the exomes of five individuals with a condition called auriculocondylar syndrome, researchers from the US, France, and Australia have found two new genes — PLCB4 and GNAI3 — that are involved in the rare craniofacial malformation syndrome, which is characterized by jaw, ear, and other abnormalities.

As they report in the American Journal of Human Genetics, both inherited and de novo mutations in the genes were detected in the study, which involved not only exome sequencing, but also confirmatory Sanger sequencing and targeted gene testing in additional ACS families. Both PLCB4 and GNAI3 code for enzymes in the same endothelin signaling pathway, the team noted, underscoring the apparent importance of the pathway in jaw formation and other facial features.

"Although ACS is rare, our findings suggest that these genes may also play a role in more common disorders of the jaw and ears," senior author Michael Cunningham, a University of Washington and Seattle Children's Research Institute researcher and medical director of the Craniofacial Center at Seattle Children's Hospital, said in a statement. "It's possible that more common jaw problems … are also caused by genes in this pathway."

An amino acid swap in a single gene is the source of blond hair in a dark-skinned South Pacific population, a Science study suggests.

An international research team did a case-control genome-wide association study involving a few dozen Solomon Islanders from opposite ends of the hair pigmentation spectrum. The search for variants linked to blond hair, a trait that naturally occurs primarily in populations from Oceania and northern Europe, led to the chromosome 9 gene TYRP1. By re-sequencing the gene, researchers found a blond hair-associated alteration in TYRP1 that replaces arginine with cystine in the resulting protein, an enzyme involved in pigmentation in humans and other mammals. While more than one-quarter of the Solomon Islanders carried this variant, which leads to blond hair when inherited recessively, the team has not found the amino acid change in other populations, suggesting blond hair has different genetic roots in Oceania than it does in northern Europe.

"[T]he human characteristic of blond hair arose independently in equatorial Oceania," co-first author Eimear Kenny, a post-doctoral researcher in co-senior author Carlos Bustamante's Stanford University lab, said in a statement. "That's quite unexpected and fascinating."

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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