Biology subjects

Carrion-Castillo, A.

Publications and source records attributed to Carrion-Castillo, A..

3 recordsLinked to original sources

bioRxiv2018

The genetics of situs inversus totalis without primary ciliary dyskinesia

Situs inversus totalis (SIT), a complete left-right mirror reversal of the visceral organs, is usually described as a recessive disorder. SIT can occur with Primary Ciliary Dyskinesia (PCD). However, most people with SIT do not have PCD, and the etiology of their condition remains poorly studied. Those without PCD may have an elevated rate of left-handedness, implying developmental mechanisms linking brain and body laterality. We sequenced the genomes of 15 people with SIT, of which six had PCD, and 15 controls. The SIT subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SIT cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SIT cases. One non-PCD SIT case had a recessive mutation in PKD1L1, which has previously been linked to SIT without PCD. However, six of the nine non-PCD SIT cases, including most of the left-handers in this dataset, had no obvious candidate genes or significant pathways affected by the mutations that they carried. While we cannot exclude a monogenic basis, more complex genetic models must also be considered, as well as environmental influences or random effects in early development.

genetics↗

bioRxiv2018

Planar cell polarity pathway and development of the human visual cortex

The radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 23,800 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (global) component was associated mainly with loci on chromosome 17 (9.5e-32 [≤] p [≤] 2.8e-10), including those detected previously as linked with intracranial volume and/or general cognitive function. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 (DAAM1; p=2.4e-34). DAAM1 is a key component in the planar-cell-polarity signaling pathway. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that, in concert with thalamocortical input to cortical subplate, DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.

neuroscience↗

bioRxiv2018

Early life factors influencing hand preference in the UK biobank cohort

Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large, general population cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, handedness was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Maternal smoking showed no association with handedness. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference. Therefore other, unknown effects must be involved, including possible environmental factors, and/or random developmental variation with respect to the left-right formation of the embryonic brain.\n\nSignificance statementLeft-right laterality is an important aspect of human brain organization which is set up early in development. Left-handedness is an overt and relatively prevalent form of atypical brain laterality. Various, often related, early life factors have been previously studied in relation to handedness, but often in small samples, or samples with biased selection schemes. Here we have performed the largest ever study of left-handedness in relation to early life factors. Left-handedness was very weakly heritable and there were significant effects of various factors such as birthweight, which remained significant after controlling for all others. However, considered all together, early life factors still had poor predictive power for the handedness of any given individual. Very early developmental perturbations, caused by environmental or chance effects in embryonic development, are therefore likely to cause left-handedness.

developmental biology↗