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Genomics In The Journals: Apr 19, 2012

NEW YORK (GenomeWeb News) – Four Nature Genetics studies explore the genetic basis of head size, brain size, and related traits.

For the first of these, the "Enhancing Neuro Imagine Genetics through Meta-analysis," or ENIGMA, consortium brought together genetic and brain imaging information on more than 21,000 healthy individuals for their genome-wide association study. The goal of the study was to find genes contributing to intracranial volume, overall brain size, and volume in the hippocampus — a brain region involved in learning and memory that tends to be smaller in older individuals and those at risk of Alzheimer's disease or certain mental illnesses.

After their discovery and replication analyses, authors of that study were left with two key SNPs, a variant linked to hippocampal volume that appears to serve as a quantitative trait locus for expression of the TESC gene and a SNP in the HMGA2 gene with apparent ties to intracranial volume and intelligence.

Hippocampal size was linked to variants at four more loci — two on chromosome 12, one on chromosome 2, and one on chromosome 9 — in a "Cohorts for Heart and Aging Research in Genomic Epidemiology," or CHARGE, consortium-led study co-authored by some of the same ENIGMA researchers.

That GWAS relied on data for more than 9,200 individuals between 56 and 84 years old who were classified as dementia-free in eight previous studies, combined with replication studies on thousands more individuals of different ages and cognitive abilities. Variants detected in that study fell in and around genes involved in apoptosis, oxidative stress, development, neural migration, and more, researchers reported. And at least one hippocampal size-associated variant showed additional ties to cognitive decline and memory loss.

In another study, members of the CHARGE consortium looked at variants involved in intracranial volume, identifying two related loci from genetic and imaging data for almost 8,200 elderly individuals.

Meanwhile, a team led by investigators from the Early Growth Genetics, or EGG, consortium focused on variants behind head circumference in infants in a fourth Nature Genetics paper.

Two chromosome 12 loci were significantly associated with head circumference in their discovery and replication groups, which included tens of thousands of infants. A third locus showed more tenuous association to infant head circumference.


A PLoS ONE study is providing additional evidence that the Tasmanian tiger or thylacine — a striped, dog-like marsupial that's been extinct since the mid-1930s — had exceptionally low genetic diversity.

Researchers from the US, Germany, and Australia did Sanger and Roche 454 sequencing on mitochondrial DNA from a dozen thylacine museum specimens before comparing the sequences to two complete thylacine mitochondrial genomes sequenced previously. Across a typically hyper-variable region of the mitochondria the team saw 99.5 percent sequence identity amongst the thylacines tested. The animals were even less diverse over 2,100 bases of sequence from other parts of the mitochondrial genome. There, sequence identity was 99.9 percent, though a few gene fragments had higher variability.

While the researchers have not yet sequenced the Tasmanian tiger's nuclear genome, they say genetic patterns found so far are reminiscent of those seen in the Tasmanian devil, another marsupial with low genetic diversity that's currently threatened by a contagious tumor disease.

"Due to the similarly poor genetic diversity of the animals, this new data suggests that the genetic health of the Tasmanian Tiger and Devil may have been affected by the geographic isolation of Tasmania from mainland Australia approximately 10-13 thousand years ago," corresponding author Brandon Menzies, a zoology researcher affiliated with the University of Melbourne and Berlin's Leibniz Institute for Zoo and Wildlife Research, said in a statement.


Breast cancer can be categorized into 10 different subgroups, according to a Nature study by researchers from the UK, Canada, and elsewhere, who used genomic and transcriptomic approaches to assess 2,000 breast tumors.

From copy number, SNP, and expression assessments of almost 1,000 clinically annotated primary tumor samples, the investigators identified 10 breast cancer subtypes with variable prognostic profiles — groupings that they confirmed using information on another 995 breast tumors. By looking at genes with altered expression in the tumor samples and their relationship to inherited variants and somatic copy number changes, the team also found genes suspected of breast cancer involvement.

"Our work provides a definitive framework for understanding how gene copy number aberrations affect gene expression in breast cancer and reveals novel subgroups that should be the target of future investigation," the study's authors concluded.


Investigators involved in a Massachusetts-led effort have tracked down 33 loci affected by balanced chromosome abnormalities in individuals with autism and related neurodevelopmental conditions.

The group used genome-wide breakpoint sequencing to test samples from 38 individuals with neurodevelopmental conditions who were known to carry some sort of balanced chromosome rearrangement — work that they describe in Cell. Some of the genes affected by the alterations had been implicated in the past studies of neurodevelopment or microdeletion syndromes, though several loci were new. Moreover, the findings hint that some of the same genes contributing to brain development and related conditions undergo alternative alterations in psychiatric conditions that appear later in life such as schizophrenia.

"[M]any of these genes play a role in diverse clinical situations — from severe intellectual disability to adult-onset schizophrenia — leading to the conclusion that these genes are very sensitive to even subtle perturbations," senior author James Gusella, director of Massachusetts General Hospital's Center for Human Genetic Research, said in a statement.


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

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