Lynn B. Jorde, Ph.D.
Professor

Contribution to Society

Limb malformation syndromes are a common group of disorders. Club foot alone is seen in approximately one in 1,000 births. Managing these syndromes typically involves multiple surgical procedures, serial casting, and physical therapy. Because features of such syndromes overlap, clinical diagnosis is often problematic. This uncertainty compromises effective treatment. Our gene mapping research will:

• Lead to more accurate diagnosis and better clinical management of these disorders
• Enable parents to make informed reproductive decisions
• Address fundamental questions about the biology of bone development

Our evolutionary genetic research will shed light on the origin of our species. This topic has generated great interest for centuries, but only in the last decade have sufficient molecular genetic data been generated to help resolve questions regarding human origins. Our studies of human genetic variation will also increase our understanding of the distribution and prevalence of genetic diseases in populations.

Research Summary

My laboratory is involved in two major areas of research: gene mapping and evolutionary genetics. Our gene mapping efforts are focused on finding genes that cause limb malformation syndromes. Currently, we are working on several of these diseases, including distal arthrogryposis, Freeman-Sheldon syndrome, Gordon syndrome, fibular hypoplasia, and ulnar-mammary syndrome. We identified mutations in a gene,TBX3, that causes ulnar-mammary syndrome. We have also demonstrated that two forms of distal arthrogryposis are caused by mutations in genes that encode two different proteins of the troponin-tropomyosin complex of fast-twitch myofibers. As our research pinpoints the responsible genes, our understanding of the etiology of these poorly understood diseases will increase, and more accurate diagnosis and prognosis will be possible. In addition, we will learn more about the biology of limb development.

Our evolutionary genetic research involves the analysis of worldwide genetic variation in human mitochondrial and nuclear DNA (including the Y chromosome). We are using these data to test a variety of evolutionary hypotheses, including the controversial proposition that modern Homo sapiens originated in Africa and then replaced human populations in other parts of the world. Although mitochondrial and nuclear polymorphisms yield somewhat discordant pictures of human evolution, our recent results show that both types of polymorphisms are consistent with an African origin of modern humans. We have also investigated genetic variation in caste and tribal populations from South India to test hypotheses about the origins and affinities of these populations.

Bamshad MJ, Wooding S, Watkins WS, Ostler CT, Batzer MA, Jorde LB (2003) Human population genetic structure and inference of group membership. Am J Hum Genet 72:578-89.

Brassington AM, Sung SS, Toydemir RM, Le T, Roeder AD, Rutherford AE, Whitby FG, Jorde LB, Bamshad MJ (2003) Expressivity of Holt-Oram Syndrome Is Not Predicted by TBX5 Genotype. Am J Hum Genet (in press).

Lum JK, Jorde LB, Schiefenhovel W (2002) Affinities among Melanesians, Micronesians, and Polynesians:
a neutral biparental genetic perspective. Hum Biol 74:413-30.

Myers JS, Vincent BJ, Udall H, Watkins WS, Morrish TA, Kilroy GE, Swergold GD, Henke J, Henke L, Moran JV, Jorde LB, Batzer MA (2002) A comprehensive analysis of recently integrated human Ta L1 elements. Am J Hum Genet 71:312-26.

Nakajima T, Jorde LB, Ishigami T, Umemura S, Emi M, Lalouel JM, Inoue I (2002) Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. Am J Hum Genet 70:108-23.

Redd AJ, Roberts-Thomson J, Karafet T, Bamshad M, Jorde LB, Naidu JM, Walsh B, Hammer MF (2002) Gene flow from the Indian subcontinent to Australia: evidence from the Y chromosome. Curr Biol 12:673-7.

Salem AH, Kilroy GE, Watkins WS, Jorde LB, Batzer MA (2003a) Recently Integrated Alu Elements and Human Genomic Diversity. Mol Biol Evol (in press)
Salem AH, Myers JS, Otieno AC, Watkins WS, Jorde LB, Batzer MA (2003b) LINE-1 preTa elements in the human genome. J Mol Biol 326:1127-46.
Sung SS, Brassington AM, Grannatt K, Rutherford A, Whitby FG, Krakowiak PA, Jorde LB, Carey JC, Bamshad M (2003) Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet 72:681-90.

Vincent BJ, Myers JS, Ho HJ, Kilroy GE, Walker JA, Watkins WS, Jorde LB, Batzer MA (2003) Following the LINEs: An Analysis of Primate Genomic Variation at Human-Specific LINE-1 Insertion Sites. Mol Biol Evol (in press).

Watkins WS, Rogers AR, Ostler CT, Wooding S, Bamshad MJ, Brassington AM, Carroll ML, Nguyen SV, Walker JA, Prasad BV, Reddy PG, Das PK, Batzer MA, Jorde LB (2003) Genetic Variation Among World Populations: Inferences From 100 Alu Insertion Polymorphisms. Genome Res (in press).

Wooding SP, Watkins WS, Bamshad MJ, Dunn DM, Weiss RB, Jorde LB (2002) DNA sequence variation in a 3.7-kb noncoding sequence 5' of the CYP1A2 gene: implications for human population history and natural selection. Am J Hum Genet 71:528-42.

Yu N, Chen FC, Ota S, Jorde LB, Pamilo P, Patthy L, Ramsay M, Jenkins T, Shyue SK, Li WH (2002) Larger genetic differences within africans than between Africans and Eurasians. Genetics 161:269-74.