Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Kovel, Carolien G.F. de; Lisgo, Steven; Fisher, Simon E.; Francks, Clyde

doi:10.1038/s41598-018-29496-2

Cited by 67 publications

(64 citation statements)

References 95 publications

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“…Assuming that hand dominance and/or division of labour between the hands is beneficial for fine motor control, then the fact that we have two hands essentially imposes a binary choice on a developmental program which may be more continuous in its original nature. The fact that human brain embryonic gene expression has been shown to be only very subtly lateralized is consistent with such a model (45,46).…”

Section: General Observationssupporting

confidence: 63%

A large-scale population study of early life factors influencing left-handedness

Kovel

Carrión-Castillo

Francks

2018

Preprint

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Running Title: Handedness and early life factors in the UK Biobank AbstractHand 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. As the developmental foundations of hand preference occur in utero, with further establishment within the first two years of life, prenatal and early-life factors are likely to play a role. Various, often related, factors have been studied in the past, but often in small samples, or samples with biased selection schemes. 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, birthweight, being part of a multiple birth, season of birth, breastfeeding, as well as sex, with each effect remaining significant after accounting for all others. Maternal smoking showed no association with handedness. Analysis of genome-wide polymorphism data indicated a tentative genetic correlation between handedness and birth-weight, which was opposite to their overall phenotypic correlation. However, the total effect on handedness of all these factors was very small. 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.

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Section: General Observationssupporting

confidence: 63%

A large-scale population study of early life factors influencing left-handedness

Kovel

Carrión-Castillo

Francks

2018

Preprint

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“…Reproducibility across samples and emerging cross-study consensus also in early development suggests a genetic influence upon cortical thickness asymmetry 58 , and genetic factors have recently been implicated in the dynamics of age-related cortical change across life 36 . One can speculate whether age-related asymmetry breakdown is a by-product of genetic factors encoding the asymmetric organization of cortex 60 supporting hemispheric specialization of function, and that this differentiation leads to downstream neural consequences in aging. Though anatomo-functional relationships are likely complex 61 , our results suggest that cortical thickness asymmetry may constitute a viable anatomical marker for key aspects of human hemispheric specialization.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

Roe

Vidal-Piñeiro

Sørensen

et al. 2020

Preprint

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Normal aging and Alzheimer's Disease (AD) are accompanied by large-scale alterations in brain organization that undermine brain function. Although hemispheric asymmetry is a global organizing feature of cortex thought to promote brain efficiency, current descriptions of cortical thinning in aging and AD have largely overlooked cortical asymmetry. Consequently, the foundational question of whether and where the cerebral hemispheres change at different rates in aging and AD remains open. First, applying vertex-wise data-driven clustering in a longitudinal discovery sample (aged 20-89; 2577 observations; 1851 longitudinal) we identified cortical regions exhibiting similar age-trajectories of asymmetry across the adult lifespan. Next, we sought replication in 4 independent longitudinal aging cohorts. We show that higher-order regions of cortex that exhibit pronounced asymmetry at age ~20 also show asymmetry change in aging. Results revealed that both leftward and rightward asymmetry is progressively lost on a similar time-scale across adult life. Hence, faster thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This simple organizational principle showed high consistency across multiple aging cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Finally, we show that regions exhibiting gradual asymmetry-loss over healthy adult life exhibit faster asymmetry-change in AD.Overall, our results suggest a system-wide breakdown in the adaptive asymmetric organization of cortex across adult life which is further accelerated in AD, and may implicate thickness asymmetry as a viable marker for declining hemispheric specialization in aging and AD. The brain becomes progressively disorganized with age, and brain alterations accelerated in Alzheimer's disease may occur gradually over the lifespan. Although hemispheric asymmetry aids efficient network organization, efforts to identify structural markers of age-related decline have largely overlooked cortical asymmetry. Here we show the hemisphere that is thicker when younger, thins faster. This leads to progressive system-wide loss of regional thickness asymmetry across life. In multiple aging cohorts, asymmetry-loss showed high reproducibility topologically across cortex and similar timing-of-change in aging. Asymmetry-change was further accelerated in AD. Our findings uncover a new principle of brain aging -thicker homotopic cortex thins faster -and suggest we may have unveiled a structural marker for a widely-hypothesized decline in hemispheric specialization in aging and AD.

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“…Gene expression and in utero ultrasound studies of human embryos have indicated that lateralized development is already underway in the human central nervous system by 5 to 8 weeks postconception, [6][7][8] which indicates a genetic-developmental program underlying the typical form of functional brain laterality. One study reported a nonsignificant heritability (<1%) for the laterality of speech sound perception, based on the dichotic listening method, and considering the full range of trait variation from left-to right-ear-advantage.…”

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confidence: 99%

Genome sequencing for rightward hemispheric language dominance

Carrión-Castillo

Haegen

Tzourio‐Mazoyer

et al. 2019

Genes Brain and Behavior

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Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.

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Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Cited by 67 publications

References 95 publications

A large-scale population study of early life factors influencing left-handedness

A large-scale population study of early life factors influencing left-handedness

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s Disease

Genome sequencing for rightward hemispheric language dominance

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