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Human Handedness: Genetics, Microtubules, Neuropsychiatric Diseases and Brain Language Areas

Akira Wiberg, Gwenaelle Douaud, Michael Ng, Yasser Al Omran, Fidel Alfaro-Almagro, Jonathan Marchini, David L Bennett, Stephen Smith, Dominic Furniss

Preprint posted on October 26, 2018 https://www.biorxiv.org/content/10.1101/454660v1

Have you ever thought about the factors that make you a right- or a left- hander? This preprint looks into the genetics of human handedness, the first genome-wide study of its kind

Selected by Jose Guerrero

Categories: genetics

Left or right? The secret (genetic) code of handedness

Lateralization and predilection for one hand may be one of the most intriguing traits of humankind. Today, only about 10% of the population is left-handed. This proportion used to be even greater a century ago when sociocultural attitudes towards lefties were quite common in western countries.

Research studies on handedness, which have included monozygotic and dizygotic twins and their siblings, have estimated a 25% heritability of this trait. In the current GWAS and big data era, we have the preprint of the first genome-wide study of handedness using more than 350,000 right-handers and 35,000 left-handers.

The most significant genetic associations with handedness are found proximal or within genes coding cytoskeletal proteins such as b-tubulin –encoded by TUBB– and microtubule-associated proteins such as Map2 and Tau –encoded by MAP2and MAPT, respectively-.  The association with MAPTis part of a large haplotype block whose lead variant lies within an intron of WNT3. This gene codes a member of the Wnt signaling pathway, highly relevant in patterning during embryogenesis and axis formation in vertebrates. In fact, these biological processes do not seem to be so far from lateralization and handedness. In line with previous GWAS, the majority of associations are found in intergenic regions and gene introns suggesting a potential role as regulatorsof gene expression. These variants could modulate the DNA’s 3D structure and affect chromatin state and interactions between distant loci and their promoters1. Indeed, the authors reference that two of the variants found are also eQTL’s of MAPTand another gene, MICB, located ~0.8 Mb downstream of TUBB, respectively.  These are exciting associations that require follow-up biological studies.However, as opposed to other GWAS where model systems are generated to explore molecular mechanisms driven by genetic variants, can biological systems be developed to address handedness?

Interestingly, this study also associates handedness with different morphological features of some areas of the brain, e.g. higher connectivity between left and right brain hemispheres in left-handers. However, is this cause or consequence of left-handers living and having been adapted to a right-handers world? Does this associate with a greater ability of left-handers to use their right hand rather than a right-hander using their left hand? Since some of the interconnected areas are related with language networks, is a correlation between handedness and language skills plausible?

Last but not least, there is also a correlation with neurological pathologies. This may not be so surprising after the association of handedness with MAPT, a locuspreviously associated with neurodegenerative disorders such as Alzheimer’s disease. MAPTencodes Tau, a protein that provides stability to axonal microtubules in neurones. Dysfunctional Tau gives rise to the so-called Tau tangles (or aggregates), which are a hallmark of Alzheimer’s disease and other neurodegenerative disorders.

As most good scientific studies, this one provides answers but also generates lots of new questions for a topic, which will continue to puzzle both the scientific and the lay world.

Further questions

Is there a specific expression pattern of the 4 selected genes in a particular brain hemisphere of left- and right- handers?

What is the prevalence of those variants through evolution and across species? Primates can also show handedness but what about quadrupeds and other vertebrates? Are the identified variants more prevalent in species that show handedness?

What about polygenic risk score for handedness? We can assume that this trait is far too complex to be genetically regulated by a limited number of variants or loci. Instead, developing a model of polygenic risk score as it has been reported for diseases such as cardiovascular disease and cancer2may be more realistic for scoring handedness.

References

1- Amartya Sanyal, Bryan R. Lajoie, Gaurav Jain, Job Dekker. The long-range interaction landscape of gene promoters. Nature  489: 109–113. 2012.

2- Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, Natarajan P, Lander ES, Lubitz SA, Ellinor PT, Kathiresan S. Genome wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genetics 50:1219-1224. 2018.

 

Posted on: 25th February 2019 , updated on: 28th February 2019

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