Biomedical subjects

Nitzan Mekel-Bobrov

Publications and source records attributed to Nitzan Mekel-Bobrov.

5 recordsLinked to original sources

PubMed2007

The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence.

Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.

Adolescent↗

PubMed2006

What makes us human: revisiting an age-old question in the genomic era.

In 1970, Karl Pribram took on the immense challenge of asking the question, what makes us human? Nearly four decades later, the most significant finding has been the undeniable realization of how incredibly subtle and fine-scaled the unique biological features of our species must be. The recent explosion in the availability of large-scale sequence data, however, and the consequent emergence of comparative genomics, are rapidly transforming the study of human evolution. The field of comparative genomics is allowing us to reach unparalleled resolution, reframing our questions in reference to DNA sequence--the very unit that evolution operates on. But like any reductionist approach, it comes at a price. Comparative genomics may provide the necessary resolution for identifying rare DNA sequence differences in a vast sea of conservation, but ultimately we will have to face the challenge of figuring out how DNA sequence divergence translates into phenotypic divergence. Our goal here is to provide a brief outline of the major findings made in the study of human brain evolution since the Pribram lecture, focusing specifically on the field of comparative genomics. We then discuss the broader implications of these findings and the future challenges that are in store.

Journal Article↗

PubMed2006

Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage.

At the center of the debate on the emergence of modern humans and their spread throughout the globe is the question of whether archaic Homo lineages contributed to the modern human gene pool, and more importantly, whether such contributions impacted the evolutionary adaptation of our species. A major obstacle to answering this question is that low levels of admixture with archaic lineages are not expected to leave extensive traces in the modern human gene pool because of genetic drift. Loci that have undergone strong positive selection, however, offer a unique opportunity to identify low-level admixture with archaic lineages, provided that the introgressed archaic allele has risen to high frequency under positive selection. The gene microcephalin (MCPH1) regulates brain size during development and has experienced positive selection in the lineage leading to Homo sapiens. Within modern humans, a group of closely related haplotypes at this locus, known as haplogroup D, rose from a single copy approximately 37,000 years ago and swept to exceptionally high frequency (approximately 70% worldwide today) because of positive selection. Here, we examine the origin of haplogroup D. By using the interhaplogroup divergence test, we show that haplogroup D likely originated from a lineage separated from modern humans approximately 1.1 million years ago and introgressed into humans by approximately 37,000 years ago. This finding supports the possibility of admixture between modern humans and archaic Homo populations (Neanderthals being one possibility). Furthermore, it buttresses the important notion that, through such adminture, our species has benefited evolutionarily by gaining new advantageous alleles. The interhaplogroup divergence test developed here may be broadly applicable to the detection of introgression at other loci in the human genome or in genomes of other species.

Adaptation, Biological↗

PubMed2005

Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.

The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose approximately 37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modern humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes.

Adaptation, Biological↗

PubMed2005

Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.

The gene ASPM (abnormal spindle-like microcephaly associated) is a specific regulator of brain size, and its evolution in the lineage leading to Homo sapiens was driven by strong positive selection. Here, we show that one genetic variant of ASPM in humans arose merely about 5800 years ago and has since swept to high frequency under strong positive selection. These findings, especially the remarkably young age of the positively selected variant, suggest that the human brain is still undergoing rapid adaptive evolution.

Adaptation, Biological↗