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New links between genes and bigger brains

A number of new links between genes and brain size have been identified by United Kingdom scientists, hopefully opening up whole new avenues of understanding brain development including diseases like dementia.

A team of scientists from both the University of Bath and the University of Lincoln in the United Kingdom, have been comparing genomes of 28 mammals with differing sizes of neocortex — that brain region involved in higher cognitive thinking such as language and decision-making. The size of the neocortex differs hugely between species. And, it is the part of the brain that has grown the most in humans over our evolutionary time on earth.

The study, published in the Royal Society journal Open Biology, identified a number of gene families — which can grow and contract through gene duplication and deletion — that have expanded in line with the growth of the neocortex relative to the size of the brain.

The research highlights a host of new genes previously not linked with brain development, including some currently known to be involved in cell signalling and immune reactions.

Researchers hope these discoveries might give us a better understanding of which genes are key to human brain growth. This information could lead to new insights into what may go wrong in a variety of mental health disorders, including dementia.

Dr Araxi Urrutia, from the Milner Centre for Evolution at the University of Bath's Department for Biology & Biochemistry, along with Dr Humberto Gutierrez from the School of Life Sciences at Lincoln University, led the research leading to the discovery of new gene families.

They found through a genome-wide analysis of amino acid composition across 37 mammalian genomes, that brain enlargement is significantly related with protein amino acid composition, although the causes of this are unclear.

"Most research on brain development uses mice as a model, but this approach could be missing some genes that are key for human brain development as our brains differ from those in mice in many aspects, most notably in the size of the neocortex.

"By comparing the genomes of many different species with large and small brains, and correlating the expansion of gene families with size of neocortex in these species, we've identified several new families of genes that could be involved in brain development in species with a large neocortex such as elephants, dolphins and, of course, ours.

"We hope this could help scientists better understand brain development and what goes wrong in conditions such as dementia."

Araxi O. Urrutia PhD, Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, UK

Researchers show that neocortical expansion is strongly associated with variations in gene family size (GFS) in mammals. The high proportion of links between GFS and brain enlargement in mammals, however, suggests changes in either is secondary to neocortex size and encephalization. Analysis of data revealed that genes in families associated with neocortex size showed significantly higher levels of expression before maximal cortical development is reached in humans, supporting a functional role for gene families in development of a large neocortex.

Among the 272 gene families whose size was correlated to neocortex expansion, 16 distinct biological gene functions and relationships were found to be significant. Among them, cell to cell signalling and increasing and/or decreasing chemical concentrations play critical roles in development and maintenance of the nervous system. Examples are Nuclear receptors (NRs) associated with gene families, and the tyrosine kinase precursor family, widely known to promote cell survival, proliferation, adhesion and migration in the central nervous system. Also, the leukotriene B4 receptor 2 family, including leukotriene B4, a proinflammatory signalling molecule which has been shown to mediate regulation of neural stem cell proliferation and differentiation

Abnormal development and degeneration of neurons has long been linked to a variety of mental health illnesses, so identifying genes associated with larger brain size helps unravel the human brain even more. These pathways may not be present in less large brained mammals, so the discovery might help fill in gaps missing from previous mouse studies.

Increased brain size is thought to have played an important role in the evolution of mammals and is a highly variable trait across lineages. Variations in brain size are closely linked to corresponding variations in the size of the neocortex, a distinct mammalian evolutionary innovation. The genomic features that explain and/or accompany variations in the relative size of the neocortex remain unknown. By comparing the genomes of 28 mammalian species, we show that neocortical expansion relative to the rest of the brain is associated with variations in gene family size (GFS) of gene families that are significantly enriched in biological functions associated with chemotaxis, cell–cell signalling and immune response. Importantly, we find that previously reported GFS variations associated with increased brain size are largely accounted for by the stronger link between neocortex expansion and variations in the size of gene families. Moreover, genes within these families are more prominently expressed in the human neocortex during early compared with adult development. These results suggest that changes in GFS underlie morphological adaptations during brain evolution in mammalian lineages.

This study was supported by a PhD CONACYT scholarship for A.C.-M and J.M.-S., a Royal Society Dorothy Hodgkin Research Fellowship (DH071902), a Royal Society research grant (RG0870644) and a Royal Society research grant for fellows (RG080272) to A.U.O. and a University of Lincoln PP grant to H.G.
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Oct 6, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Large brains appear several times in diverse mammal species. Examples are illustrated
here for each major mammal group. Mammalian brain radiation pictured above is based on
the findings of Murphy et al. and Kaas. Brain images are from the University of Wisconsin
and Michigan State Comparative Mammalian Brain Collections (www.brainmuseum.org).

Image Credit:
Suzana Herculano-Houzel, Instituto de Ciências Biomédicas


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