Bruce Lahn, Ph.D.

Mammalian genetics, development and function of the brain, and comparative and evolutionary genomics

Research Summary

Our laboratory is interested in developing and applying innovative genetic approaches to the study of mammalian development and evolution, with an emphasis on the brain. The following is a sampling of our diverse research interests:

1. Genetic basis of human brain evolution
One of the ultimate quests in biology is to understand the molecular basis underlying the distinct cognitive capacity of the human brain. Our lab investigates this question by an evolutionary approach, where we systematically compare sequences and expression patterns of brain-related genes between humans and other mammals. The techniques we employ include high-throughput sequencing and microarray-based expression analysis. Through these comparative studies, we have identified candidate “human-ness” genes, which appear to have undergone distinct evolutionary changes in the human lineage relative to other mammalian lineages. Through further investigation of these genes, we hope to uncover genetic basis that underlie unique functional properties of the human brain.

2. Computational genomics and bioinformatics
With the deciphering of the human genome and the genomes of numerous other organisms, vast amounts of DNA sequences are becoming available. Much needed now is in-depth analysis of these sequences to identify patterns that inform about genome function and evolution. Recognizing this, we are developing computational tools to perform large-scale analysis of genome sequence and gene expression. Such analysis is beginning to shed light on many important questions, such as how gene families grow and diversify, how mutation rate affects the evolution of proteins, and how changes in protein sequence and expression pattern translate into phenotypic evolution.

3. Isolating genes that control early brain development
To understand the molecular mechanisms controlling cell differentiation and migration during the early stages of brain formation, we are systematically isolating genes differentially expressed during different stages of mouse cortical development. We are utilizing two approaches to identify such genes: cDNA subtraction and microarray-based expression analysis. Following the identification of differentially expressed genes, detailed functional analysis is carried out on a selected subset of the genes.

4. Identifying the genetic basis of neurodegeneration
We are currently working on a mouse model of neurodegeneration. This model, known as nm1952, develops tremor, ataxia and deficits in motor strength. Pathologically, nm1952 mice develop inclusion bodies (protein aggregates) in several brain regions, including the deep nuclei of the cerebellum, pons, medulla, and spinal cord. Inclusion bodies are a hallmark of many human neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s diseases. The mutant gene in nm1952 mice was unknown previously. We have positionally cloned the nm1952 gene, and shown that it encodes a novel cytoskeletal protein. Further function studies of this gene is currently underway. The nm1952 mouse provides a model for investigating human neurodegenerative diseases.

5. New technologies in mouse transgenics
We are developing set of powerful transgenics technologies to study the mouse central nervous system. A key feature of these new technologies is their exceptional versatility. Collectively, they offer a wide variety of means to interrogate the mouse CNS, including 1) conventional and conditional knockout of specific genes, 2) epitope tagging of endogenous proteins encoded by targeted genes, 3) monitoring of gene expression in vivo, 4) fate mapping of particular cell lineages, 5) ablation of specific cell types, and 6) visualization of neuronal circuitry. These new technologies offer unprecedented power in dissecting the molecular mechanisms controlling CNS development and function. We are currently employing these technologies to study early brain development.

6. Searching for defining features of stem cells
Stem cells are unique cell populations capable of regenerating themselves as well as other cell types. We are interested in identifying the defining molecular features that distinguish stem cells from differentiated cells. Specifically, we are testing the hypothesis that stem cells of different lineages, as diverse they may appear, share certain characteristics in common, such as the expression of certain genes, or the manner by which transcription is globally regulated. We are currently employing microarray and other technologies to interrogate gene expression and chromatin structure in stem cells at the whole-genome level.

7. Induction of stem cell differentiation along desired lineages
Stem cells have the potential to differentiate into a wide variety of cell types. As such, they hold great promises for transplantation therapy. Yet, by in vitro means, it has been very difficult to differentiate stem cells into therapeutically useful tissues. We are exploring in vivo methods to differentiate stem cells along desired lineages. Because of the complexity and developmental relevance of the in vivo environment, differentiation of stem cells into specified tissues and organs may occur more readily and with greater precision. Working with several types of stem cells, including ES, EG and mesenchymal stem cells, we hope to ultimately translate our research into transplantation-based therapeutic applications, such as tissue repair and organ replacement.

Selected Papers

Wyckoff GJ & Lahn BT. Mutation-driven evolution of protein sequences. (submitted)

Wyckoff GJ, Dorus S, Wu C-I & Lahn BT. Higher pace of protein evolution in primates relative to rodents. (submitted)

Lahn BT, Tang ZL, Zhou J, Barndt RJ, Parvinen M, Allis CD & Page DC. Previously uncharacterized histone acetyltransferases implicated in mammalian spermatogenesis. PNAS 13:8707 (2002)

Honarpour N, Gilbert SL, Lahn BT, Wang X & Herz J. Apaf-1 deficiency and neural tube closure defects are found in fog mice. PNAS 98:9683 (2001)

Lahn BT, Pearson NM & Jegalian K. The human Y chromosome, in evolution’s light. Nature Reviews Genetics 2:207-216 (2001)

Jegalian K & Lahn BT. Why the Y is so weird? Scientific American 284(2):56 (Feb. 2001)

Lahn BT & Page DC. A human sex-chromosomal gene family expressed in male germ cells and encoding variably charged proteins. Human Molecular Genetics 9:311 (2000)

Lahn BT & Page DC. Four evolutionary strata on the human X chromosome. Science 286: 964 (1999)

Lahn BT & Page DC. Retroposition of autosomal mRNA yielded testis-specific gene family on human Y chromosome. Nature Genetics 21:429-433 (1999)

Lahn BT & Page DC. Functional coherence of the human Y chromosome. Science 278:675-680 (1997)