Genome-wide association study identifies susceptibility loci for dengue shock syndrome

The first genome-wide association study for dengue shock syndrome (DSS) identified SNPs at two loci, MICB and PLCE1, associated with this disease. Previous epidemiological studies found that some groups of people are more susceptible to dengue shock syndrome, possibly pointing to a genetic influence. This study compared the genomes of 2,008 pediatric cases of DSS against 2,018 control genomes in Vietnam. Another GWAS study was performed after the first with 1,737 DSS patients against 2,934 controls in order to validate their results. Two loci, MICB and PLCE1, were found to be associated with DSS patients as opposed to the controls, which suggests that dengue susceptibility might be influenced by genetic factors.

The genetic basis of 130 brain diseases

Like in the cases of Prader-Willi Syndrome and Angelman Syndrome which are both based upon changes in the same locus, it appears that there are many instances of single genes that are implicated in multiple psychological disorders. Last year, the Gene to Cognition project finished their search for proteins involved in the postsynaptic density (the PSD: a molecular machinery involved in synaptic development and function), resulting in a list of 1461 genes, many of which are already associated with psychological disorders. Specifically, 130 diseases are now known to be linked to proteins critical to the PSD, and many of those proteins have been shown to play a role in multiple diseases. With this list of genes and proteins, it will now be possible for scientists to begin designing better therapies for disease, and perhaps creating therapies that may function in multiple diseases with similar genetic bases. It will be interesting to see how many of these disorders seem to be caused by deletions and epigenetic factors like those seen in the readings for this week and how many can be understood by more classical, Mendelian inheritance patterns.

Genetics and pathogenesis of inflammatory bowel disease

This study looked at the genetics of inflammatory bowel disease (IBD) which arises from an excessive inflammatory response to microbes in the bowel. Healthy food metabolism depends on the co-evolution of the bacteria inhabiting our guts and our immune system; when these two fall out of since, our immune systems attack these helpful bacteria. Using GWAS, 99 different genetic risk loci (28 of which are similar to Crohn's disease) indicating the two arise from problems in the same pathway. The two forms of IBD, childhood-onset and adult-onset, seem to have similar genetic origins, implying other genetic, environmental, and epigenetic contributions to the disease. In addition, there is a weaker association between monozygotic twins having IBD than Crohn's disease (10-15% vs 30-35%). Some of the genes suspected to be involved in both Crohn's disease and IBD are those responsible for barrier function, microbial defense, innate immune regulation, regulation of adaptive immunity, ER stress and metabolism. The frequency of different variants of the disease varies in different populations indicating selective pressures of different environments. This study highlights the proteins involved in the digestive pathway, in addition showing promise for early disease diagnosis and treatment.

Earlier dispersal of modern humans in Europe

Two new studies published yesterday in Nature together suggest that anatomically modern humans may have reached Europe a few thousand years earlier than previously thought. While examples of Aurignacian culture had helped us arrive at a date of approximately 43-42 kyBP for the arrival of AMHs in Europe, physical human evidence dated only to 41 kyBP at the earliest. One study reanalyzed two molars found in Italy in 1964. The molars had long been described as Neanderthal, but have only now been shown to be human through "two independent morphometric methods based on microtomographic data." The molars were dated to 45-43 kyBP. The other study revisited a maxilla, KC4, discovered in a British cave in 1927. Originally underestimated to 36-34 kyBP, researchers dated KC4 to 44.2-41.5 kyBP. The molars and KC4 now represent the oldest evidence of AMHs in all of Europe and in northwestern Europe, respectively. These findings suggest a rapid expansion of humans into Europe before the disappearance of the Neanderthals, adding fuel to the fire of the human-Neanderthal admixture debate.

The "Sixth Nucleotide" and it's epigenetic role in the brain

This is a really interesting article about the "sixth nucleotide" which was discovered about 2 years ago. Related to 5-methylcytosine (5-mc), 5-hydroxymethylcytosine (5-hmc) may have a different function in epigenetics as compared to it's derivative; specifically, it's been implicated in DNA methylation plasticity.

This study, coming out of Emory University, quantified 5-hmc in the brain (it's enriched compared to other tissues - at around 40%) and mapped 5-hmc genome-wide in mouse cerebellum and hippocampus cells from postnatal development through adulthood. 5-hmc seems to be enriched on active genes (in contrast to 5-mc), and regions controlled by 5-hmc revealed both stable and dynamically modified loci during the period of development and aging. The team is now focusing on mapping how 5-hmc changes during development and its relationship to neurological disorders such as Rett syndrome and autism.

You can read the synopsis on Science Daily.

More of the same: getting down with the Denisovans

Researchers from Uppsala University have found evidence for genetic affinity between South East Asians and Denisovans. Instead of comparing whole genomes, they utilized genotype data for many populations and ran a sophisticated model to assess how ascertainment bias (i.e. rare SNPs not being included) could affect signals of archaic admixture. Their study included more than 1,500 samples from geographically disparate regions. Their results indicated genetic admixture among East Asians, and higher genetic affinity between Denisovans and Oceanians (previously known) as well as South East Asians.

The role of genetic variation in the causation of mental illness: an evolution-informed framework

This paper is a review of some of the leading hypothesis for why mental disorders are present in high numbers in populations and have not been selected against. Uher focuses specifically on fitness reducing illnesses, such as schizophrenia, autism, anorexia nervosa and biopolar disorder, among others. The persistence of these diseases is a paradox in that fitness reducing genetic variants should be under strong negative selection, however studies have shown that these diseases are highly heritable. Uher concludes that a model of polygenic mutation-selection balance best explains this paradox. Because human mental health and brain function is controlled by a large number of genes and processes, and most mutations that contribute to mental illness are newly arising, environmental factors and the cumulative effects of mildly pleiotropic genes could be responsible. It should be noted that Uher does not entertain any epigenetic contributions to mental disease in this review.