We are a mammalian biology lab interested in two major research topics: 1) evolutionary genetics, especially the genetic basis of human brain evolution, and 2) stem cell biology. Our other research interests include neurogenetics, bioinformatics, and developing technologies for high-throughput functional genomics.

1. Genetic Basis of Human Brain Evolution

As a species, Homo sapiens exhibits many marked distinctions from other mammals. Particularly notable is the human brain, which is far larger and more complex than that of all other species. As a result of the highly evolved brain, humans are endowed with a rich and sophisticated behavioral repertoire that includes language, tool use, self-awareness, symbolic thought, and cultural learning.

Obviously, the distinct biological properties of the human brain are the product of genetic changes accumulated over the evolutionary history of Homo sapiens. We explore such genetic basis of human brain evolution using a variety of approaches — ranging from genomics, bioinformatics, and population genetics, to biochemistry, cell biology, and animal models.

1a. Accelerated evolution of brain genes in the descent of Homo sapiens

To address whether the evolution of the human brain has left genome-wide genetic imprints, we systematically examined the evolutionary history of genes implicated in diverse biological aspects of brain function. This analysis showed that, on average, protein sequences of brain-related genes have evolved more rapidly in primates than in other mammalian taxa, and that this accelerated evolution is most dramatic along the lineage leading to humans. Moreover, when examining only the subset of genes that function predominantly in brain development, the high rate of evolution in the human lineage becomes even more pronounced.

The above results argue that the remarkable phenotypic evolution of the human brain is correlated with accelerated evolution in the protein-coding regions of the underlying genes, particularly those involved in brain development. These results also argue that the accelerated evolution, visible across many genes, likely reflect the accumulation of a large number of advantageous mutations scattered across many brain-related genes in the course of primate and human evolution.

1b. Identification of candidate “humanness” genes

Another major objective of our research is to identify specific “humanness” genes that might have been particularly relevant to human brain evolution. We start with large-scale comparisons of genes across multiple species to identify “outliers” in the genome — i.e., genes exhibiting a rate of evolutionary changes in the human lineage that is significantly greater than that of the other mammalian lineages. We then subject these outliers to a set of more detailed and statistically rigorous analyses to examine whether their molecular evolutionary history is indeed consistent with the action of positive selection in primates and especially the human lineage.

Employing the above strategy, we identified a number of candidate genes that might have played a role in human brain evolution. Examples include ASPM, Microcephalin, CDK5RAP2, CENPJ, Sonic Hedgehog, APAF1, and CASP3. A remarkable theme unifying all these genes is their involvement in determining neuronal cell number and brain size during embryonic development. When any one of these genes is mutated in either human or mouse, the result is a dramatically reduced brain size. For a subset of these genes, reduction in brain size appears to be the only discernable defect in the organism, indicating a highly specific function of the genes in regulating brain size. These findings led us to postulate that that genes controlling brain size during development might have played a particularly important role in transforming brain size during evolution.

Currently, we are conducting functional analyses of these genes in the hope of understanding the exact mechanisms by which molecular evolution of these genes altered developmental processes in the brain. We have undertaken a variety of approaches, including in vitro assays of gene function and in vivo gene replacement experiments whereby the human gene is used to substitute its ortholog in the mouse.

1c. Is the human brain still evolving?

The most salient trend in the evolutionary history of Homo sapiens is the rapid increase of brain size and complexity. Could this trend be continuing even in present-day humans? To address this question, we focused on the candidate “humanness” genes discussed above, and used population genetics tools to search for evidence of ongoing adaptive evolution of these genes in present-day humans. We reasoned that if a gene has evolved adaptively in the making of the human species, it may well continue to undergo adaptive evolution even after the emergence of anatomically modern humans. By analyzing human polymorphism patterns, we found evidence that some of these genes are experiencing ongoing positive selection in humans.

Of particular interest are the ASPM and Microcephalin genes. In each of these two genes, a new sequence variant arose in the recent past of human history, and has since swept to exceptionally high frequency around the world, presumably due to strong positive selection operation on the new variant. We do not yet know the exact fitness advantage conferred by these new variants. However, given the highly specific function of ASPM and Microcephalin in regulating brain size and also given their history of intense adaptive evolution in the lineage leading to Homo sapiens, it is reasonable to hypothesize that these new variants segregating in modern humans may improve some aspect of brain function. Work is currently underway to test this hypothesis. These findings suggest the tantalizing possibility that the human brain is still evolving, in the sense that is still undergoing rapid adaptive changes.

2. Stem Cell Biology

Another major thrust of our research is stem cell biology. We are interested basic cell biological questions such as what gives stem cells their “stemness” and what are the functions of adult stem cells. We are also interested in therapeutic applications of stem cells. 

2a. Molecular basis of “stemness” vs. “differentiatedness”

We wish to understand the molecular mechanisms that render pluripotency to stem cells, or conversely, restricted phenotype to differentiated cells. Our working hypothesis is that, as stem cells differentiate during development, the progressive restriction of cell fate is achieved, at least in part, by secluding key regulatory genes from the cell’s transcriptional machinery. We further hypothesized that different types of differentiated cells acquire a different set of secluded genes. We have devised a novel experimental protocol to systematically identify genes that undergo such seclusion in a particular differentiated cell type. We found that secluded genes tend to be master regulators involved in triggering the differentiation of alternative cell fates. For example, in fibroblasts, genes undergoing seclusion may include transcription factors that promote muscle differentiation or neural differentiation. The simplest interpretation is that, by secluding these master triggers of alternative cell fate, fibroblasts can stably maintain their fibroblast identity. Methods that could induce secluded genes to be reactivated might allow de-differentiation or trans-differentiation of otherwise terminally differentiated cells.

2b. Function of adult stem cells

In has been recognized in recent years that many non-regenerative adult tissues previously thought be devoid of stem cells do indeed harbor stem cells. The best examples are brain and heart, for which stem cells persist into adulthood although neither organ undergoes significant regeneration in the adult. What is the function of adult stem cells in these tissues then? Some studies suggest that they may facilitate low levels of regeneration; other studies suggest a role in repairing damages from catastrophic insults. These studies notwithstanding, the function of adult stem cells remain poor understood. Our lab has undertaken several approaches to study adult stem cells. One involves the construction of complex transgenic systems in mice with which it would be possible to closely monitor the physiological behavior of adult stem cells under both normal and stressful conditions. Another approach involves knocking out genes previously implicated in the function of adult stem cells. The combination of these two approaches provides a powerful tool to dissect the function of stem cells in adults.

2c. Therapeutic potential of stem cells

Besides basic research on stem cell mechanisms, we are also exploring potential applications of stem cells in therapy. We use both in vitro and in vivo approaches to develop methods to differentiate stem cells into desired cell types. We are also testing the therapeutic potential of stem cells in animal models. A lot of our therapeutically oriented stem cell work is done in collaboration with the Center for Stem Cell Biology and Tissue Engineering at Sun Yat-sen University , China .

3. Other Research Interests

In addition to the research interests described above, our lab is also active in a few other areas. One example is neurogenesis, where we investigate how the homeostasis of GABA_A receptors in neurons is regulated. Another example is the development of a new technology for accurate and high-throughput gene expression analysis in single cells. While these various research interests may seem disparate, they are united by the overarching goal of understanding mammalian development and evolution, especially of the brain.

Complete list of publications with PDF files for download

Selected Publications

Vallender TW & Lahn BT. Localized methylation in the key regulator gene endothelin-1 is associated with cell type-specific transcriptional silencing. FEBS Letters, 580:4560 (2006).

Dorus S, Anderson JR, Vallender EJ, Gilbert SL, Zhang L, Chemnick LG, Ryder OA, Li W & Lahn BT. Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates. Human Molecular Genetics, 15:2031 (2006).

Gilbert SL, Zhang L, Forster M, Anderson JR, Iwase T, Soliven B, Donahue LR, Sweet HO, Bronson RT, Davisson MT, Wollmann RL & Lahn BT. Trak1 mutation disrupts GABA_A receptor homeostasis in hypertonic mice. Nature Genetics, 38:245 (2006).

Choi SS, Li W & Lahn BT. Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis. Nature Genetics, 37:1367 (2005).

Mekel-Bobrov N, Gilbert SL, Evans PD, Vallender EJ, Anderson JR, Hudson RR, Tishkoff SA & Lahn BT. Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens. Science, 309:1720 (2005).

Evans PD, Gilbert SL, Mekel-Bobrov N, Vallender EJ, Anderson JR, Tishkoff SA, Hudson RR & Lahn BT. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science, 309:1717 (2005).

Gilbert SL, Dobyns WB & Lahn BT. Genetic links between brain development and brain evolution. Nature Reviews Genetics, 6:581 (2005).

Wyckoff GJ, Malcom CM, Vallender EJ & Lahn BT. A highly unexpected strong correlation between fixation probability of nonsynonymous mutations and mutation rate. Trends in Genetics, 21:381 (2005).

Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM & Lahn BT. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell, 119:1027 (2004).

Dorus S, Evans PD, Wyckoff GJ, Choi SS & Lahn BT. Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity. Nature Genetics, 36:1326 (2004).

Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S & Lahn BT. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Human Molecular Genetics, 13:489 (2004).

Choi SS & Lahn BT. Strong positive selection in the evolution of MRG, a neuron-specific gene family implicated in nociception. Genome Research, 13:2252 (2003).

Dorus S, Gilbert SG, Forster M, Barndt RJ & Lahn BT. The CDY-related gene family: coordinated evolution in copy number, expression profile, and protein sequence. Human Molecular Genetics, 12:1643 (2003).