Resumen de Deciphering adaptation in the human genome: The case of caSR in south-east Asian hunter-gatherers
- español
Los cazadores recolectores del Sudeste Asiático presentan varias características fenotípicas especificas como un color de piel particularmente oscuro (O), una estatura extremadamente baja (B), un pelo muy rizado (R) y una inusual acumulación de grasa en las caderas llamada esteatopigia (E) (fenotipo OBRE). A partir de la recopilación y análisis de secuencias genómicas completas de varias poblaciones humanas de las Islas Andamán, Malasia, y Filipinas, identificamos señales de selección positiva alrededor del gen del receptor de detección de calcio (abreviado como CaSR en inglés)), y la sustitución no sinónima R990G como variante genética potencialmente adaptativa en estas poblaciones para validar experimentalmente. A nivel sistémico el CaSR actúa sobre la homeóstasis del calcio regulando la secreción de la hormona paratiroidea. Además, el gen se expresa en muchos tejidos y participa en diferentes funciones biológicas. Consecuentemente, para poder investigar el fenotipo adaptativo a nivel de organismo, generamos a un ratón knock-in por la sustitución R990G usando la tecnología del CRISPR-Cas9 y analizamos las posibles diferencias fenotípicas relacionadas con las funciones del CaSR entre los animales homocigotos por el alelo ancestral y derivado. Encontramos que los homocigotos 990G muestran, entre otros fenotipos, mayor peso y una mayor acumulación de grasa probablemente relacionada con cambios en el equilibrio adipogénesis-lipolisis. Estas características podrían facilitar una maduración sexual temprana, de acuerdo con la hipótesis que la baja estatura del fenotipo OBRE puede ser el resultado de la selección para un inicio temprano de la reproducción en un ambiente particularmente hostil.
- English
Studying human diversity has interested researchers and explorers for centuries. Only in the last decades with the increasing amount of first genetic and later genomic data, scientists have been able to appreciate the high genetic similarity of all human populations (more than 99 % identity) and retrace human migrations through molecular fingerprints left in our genomes. Besides, results obtained from the Population Genetics field suggest that populations are melted into one another, their allele frequency variation is not discrete, but rather clinal and it is strongly affected by selective pressures experienced by populations in different environments.
In this thesis, we focused on the study of human adaptation in the tropical rainforest environment. Specifically, we analyzed tribal rainforest hunter-gatherer populations from South East Asia presenting certain morphological features including a particularly dark skin color (D), an extremely short stature (S), the development of woolly hair (W), and the presence of a marked fat accumulation localized in the hips called steatopygia (S) (DSWS phenotype). Analyzing whole-genome data from the Andamanese population, we retrieved signals of selection in the region encompassing the Calcium-sensing Receptor (CaSR). Here, the non-synonymous substitution R990G (rs1042636) was identified as one of the top 20 most differentiated non-synonymous variants between the Andamanese and mainland Indian populations showing signals of selection in the former group. Furthermore, we replicated the selection signal in the CaSR region in whole-genome data from Malaysians and Philippine populations also carrying the R990G substitution at high frequencies. Thus, we decided to study the phenotypic implication of the R990G substitution in a mouse model considering the following evidence in addition to the selection signals previously described: the R990G substitution was associated with a very high CADD score (18,42), indicating a strong functional impact; the substitution was also previously described as a gain of function, conferring the receptor higher sensitivity to extracellular Ca2+; the CASR gene is very pleiotropic, and it shows an active role in different biological pathways.
Results obtained from the mouse model showed a systemic unbalance in the lipid handling, being the homozygotes for the derived allele more prone to develop higher weight and BMI, higher fat percentage, higher number of small adipocytes in fat histology, and downregulation of lipolytic-related genes.
All the evidence gathered in this study suggests that the R990G substitution in rainforest hunter-gatherers from South East Asia favors an enhanced fat accumulation that could result adaptive in a difficult environment such as the tropical rainforest. In this line, the increased fat storage enhances energy storage and has been previously shown to result in a faster sexual maturation and early onset of menarche in girls, generating an anticipated closure of the growth plate in bones. Thus, we hypothesize that natural selection favored this mechanism in rainforest hunter-gatherer populations studied here generating their specific phenotype with a small stature and the development of the steatopygia.
When studying human adaptation in historically excluded populations, their social background and possible consequences of the research must be considered. Often, adaptation generates extreme phenotypes that have been historically used to racialize people and confine them to a life of social exclusion based on the assumption that the phenotype mirrored the psychological and moral qualities of individuals.
For these reasons, some considerations must be pointed out: neither clinal population differences nor any adaptative variants are enough to justify any kind of subdivision of the human race into biological discrete groups; any kind of deterministic association between genetics and psychological abilities or ethical values must be condemned, being the result of the resurrection of some old-fashioned nationalistic ideas; science and society are strictly interdependent, while on one hand, scientists are human beings socialized in a certain environment which could be influencing their research, on the other hand, the study of human diversity from a scientific perspective has a strong impact on public opinion and politics, giving scientists the strong responsibility to design collaborative and respectful projects and disseminate consciously their scientific results.
