The Genetic Secret Behind Human Skull Morphology

Researchers at the Universities of Helsinki, Barcelona, and Tokyo Medical and Dental University (TMDU) have discovered a single nucleotide alteration that is crucial to the evolution of human skull morphology and influences the expression of the TBX1 gene and the formation of the skull base.

When compared to other closely related hominin species and primates, humans, or Homo sapiens, have distinct characteristics. One such feature is the shape of the base of the skull. The larger brains have evolved as a result of major evolutionary changes that underlie these features.

A team from Tokyo Medical and Dental University (TMDU), the University of Helsinki, and the University of Barcelona has now examined a genomic variant in charge of this particular human skull base morphology in a study just published in the American Journal of Human Genetics.

The majority of the genomic alterations that took place during the evolution of humans happened in areas that control and regulate gene expression rather than directly in the genes themselves. Genetic conditions frequently result from variations in these same regions, which cause aberrant gene expression throughout development. Thus, it is essential to recognize and describe these genomic alterations in order to comprehend human development and illness.

The evolution of Homo sapiens relied heavily on the development of the basicranial region or the base of the skull, where it joins the neck bones. This allowed for the development of a highly flexed skull base, which in turn allowed for an increased brain size. Variants that impact this region's development are probably very important to human evolution.

Initially, the group looked for variations in a single DNA letter, known as single nucleotide polymorphisms (SNPs), that resulted in distinct gene regulation in the basurane region of Homo sapiens in contrast to other extinct hominins. Among these SNPs, one that is situated in the gene TBX1 stood out.

The SNP, known as “rs41298798,” was then demonstrated to be located in a region that controls the expression levels of the TBX1 gene using cell lines. The “ancestral” form of the SNP, which was found in extinct hominins, is linked to lower levels of TBX1 expression, whereas the form found in Homo sapiens results in higher levels of TBX1.

We then employed a mouse model with lower TBX1 expression, which resulted in distinct alterations to the morphology at the base of the skull and premature hardening of a cartilage joint where the bones fuse together, restricting the growth ability of the skull.”

Noriko Funato, Study Lead Author, Tokyo Medical and Dental University

The changes in the Tbx1-knockout mice were reminiscent of the known basicranial morphology of Neanderthals.

The significance of this genetic variant in the evolution of distinct skull base morphology is further demonstrated by the fact that these morphological changes are also reflected in human genetic conditions associated with lower TBX1 gene dosage, such as DiGeorge syndrome and velocardiofacial syndrome.

The discovery of this genomic variant opens the door to a better understanding and treatment of common genetic conditions linked to decreased expression of the TBX1 gene, as well as to new insights into human evolution.