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Genomics in the Journals Jul 24, 2014

NEW YORK (GenomeWeb) – In Nature Genetics, members of the Marmoset Genome Sequencing and Analysis Consortium presented the first genome sequence established for the common marmoset, Callithrix jacchus, a diminutive New World monkey species.

The team put together a 2.26 billion base marmoset genome assembly using sequences generated from female marmoset DNA with a combination of Sanger and high-throughput sequencing methods.

The researchers went on to analyze and compare the genome with sequences from apes and Old World monkeys in the hopes of understanding key marmoset features — from the marmoset's growth and rapid reproduction to its frequent twinning and the between-twin chimerism that occurs when non-identical marmoset twins swap hematopoietic stem cells in utero. In the sequenced female, for example, they detected male co-twin DNA, which made up roughly one-tenth of reads in the resulting reference genome.

Though such chimerism can be detrimental in other animals, it does not appear to negatively affect marmosets, the study authors noted. Likewise, the marmoset's propensity for twinning — which appears to be regulated by WFIKKN1 and other genes — is of interest for understanding reproduction processes in primates, including humans.

"The translational implications of this work to pregnancy and reproductive medicine are significant," Baylor College of Medicine obstetrics, gynecology, and fetal medicine researcher Kjersti Aagaard, a study co-author, said in a statement. "Given the relatively high rate of complications of twins we see [in humans] … it is crucial to understand the underlying adaptive biology of the marmoset which enables them to avoid these complications."

Common variants play a particularly pronounced role in the heritability of autism spectrum disorder, according to another Nature Genetics study done by investigators at Carnegie Mellon University, Mount Sinai's Icahn School of Medicine, and elsewhere.

The team did array-based common variant genotyping on more than 3,000 individuals with and without autism who had been enrolled through the Population-based Autism Genetics and Environment Study, or PAGES, over more than two decades.

From the genotyping data gleaned from that population-based study of ASD, combined with new statistical analysis methods, the researchers estimated that autism has more than 52 percent heritability. But despite the elevated rates of rare, de novo mutations that have been described in the genomes of individuals with ASD, the results of their analysis indicated that those mutations contribute just 2.6 percent to disease risk variance.

In contrast, the team argued that common variants, each contributing little to ASD risk individually, add up to influence a large portion of the heritability that was accounted for in the study.

"Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture," co-corresponding author Joseph Buxbaum, a psychiatry, genetics, and genomics researcher with the Icahn School of Medicine, said in a statement. "Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together."

Researchers from the Schizophrenia Working Group of the Psychiatric Genomics Consortium performed a large, multi-stage genome-wide association study aimed at identifying genetic contributors to that highly heritable psychiatric condition — work they described in Nature.

The team started with genotyping profiles for 32,241 individuals with schizophrenia and 45,604 controls who had been enrolled for past studies in European or East Asian populations, imputing additional variants in the case and control genomes using 1,000 Genomes Project data.

Results from that discovery set pointed to a polygenic risk profile for schizophrenia, the researchers reported, highlighting hundreds of suspicious SNPs in the genome. When they folded in information on 1,235 trios — representing children with schizophrenia and their parents — they found a trend toward risk SNP transmission from parents to children.

A closer look at the distribution of the independent schizophrenia-associated SNPs revealed 108 apparent risk loci, including sites near neurotransmitter genes and other candidates implicated in schizophrenia in the past, and 83 new loci.

The risk loci included sites falling in and around genes with higher-than-usual expression in the brain or immune-related tissues, the study's authors noted, and in enhancer regions for genes important to brain or immune function.

"We now have new biological mechanisms that we and fellow researchers can explore as we attempt to develop new treatments," corresponding author Michael O’Donovan, a neuropsychiatric genetics and genomics researcher at Cardiff University, said in a statement.

A Nature study described more than 100 loci linked to the age when females begin menstruating during puberty, known as menarche. The timing of this event can vary dramatically from one individual to the next, the authors of the study noted, and appears to track with risk of obesity, cardiovascular disease, type 2 diabetes, breast cancer, overall mortality, and more.

To delve into the genetic factors behind the known heritability involved in age at menarche, investigators from the ReproGen Consortium used genome-wide arrays to genotype almost 133,000 women of European ancestry whose age of menarche was known. To that, they added custom genotyping array data on more than 49,000 European women profiled at a smaller set of SNPs with tenuous ties to age of menarche in past GWAS.

Starting from more than 3,900 SNPs with genome-wide significant ties to age of menarche onset, the team narrowed in on 123 independent signals at 106 new or previously known sites in the genome.

The set included loci linked to other puberty-related traits, body mass index, and certain diseases, researchers reported, with variants tending to occur in and around sequences for genes from receptor signaling and nuclear hormone receptor pathways.

The group also saw over-representation of age at menarche-associated variants in parts of the genome known for imprinting, which leads to expression of either paternal or maternal alleles, suggesting imprinting can affect features of puberty and related traits.