Human Handedness: Genetics, Microtubules, Neuropsychiatric Diseases and Brain Language Areas
Preprint posted on October 26, 2018 https://www.biorxiv.org/content/10.1101/454660v1
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.
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.
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 2019Read preprint
Also in the genetics category:
The Hunchback temporal transcription factor determines motor neuron axon and dendrite targeting in Drosophila
|Selected by||Abagael Lasseigne|
Preformed Chromatin Topology Assists Transcriptional Robustness of Shh during Limb Development
|Selected by||Rafael Galupa|
Molecular Logic of Spinocerebellar Tract Neuron Diversity and Connectivity
|Selected by||Yen-Chung Chen|
Over-activation of BMP signaling in neural crest cells precipitates heart outflow tract septation
|Selected by||Giulia Boezio|
Functional dissection of TADs reveals non-essential and instructive roles in regulating gene expression
|Selected by||Clarice Hong|
Crowdfunded whole-genome sequencing of the celebrity cat Lil BUB identifies causal mutations for her osteopetrosis and polydactyly
|Selected by||Jesus Victorino, Gabriel Aughey|
Dynamic Erasure of Random X-Chromosome Inactivation during iPSC Reprogramming
|Selected by||Sergio Menchero|
Kinesin-6 Klp9 plays motor-dependent and -independent roles in collaboration with Kinesin-5 Cut7 and the microtubule crosslinker Ase1 in fission yeast
|Selected by||I. Bouhlel|
The Spatio-Temporal Control of Zygotic Genome Activation
|Selected by||Meng Zhu|
Multilevel regulation of the glass locus during Drosophila eye development
|Selected by||Gabriel Aughey|
Distinct ROPGEFs successively drive polarization and outgrowth of root hairs
|Selected by||Marc Somssich|
A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila
|Selected by||Natalie Dye|
MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts
|Selected by||Katie Weiner|
Super-resolution Molecular Map of Basal Foot Reveals Novel Cilium in Airway Multiciliated Cells
|Selected by||Robert Mahen|
Single cell RNA-Seq reveals distinct stem cell populations that drive sensory hair cell regeneration in response to loss of Fgf and Notch signaling
Distinct progenitor populations mediate regeneration in the zebrafish lateral line.
|Selected by||Rudra Nayan Das|
The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility
|Selected by||Gabriel Aughey|