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| Bruce T. Lahn, Ph.D. Professor Howard Hughes Medical Institute Department of Human Genetics Committee on Genetics Committee on Evolutionary Biology Committee on Neurobiology |
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| Genetic
basis of human brain evolution & stem cell biology
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 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 GABAA 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.
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