About a fifth of the human gene pool belongs largely either to Indo-European or Dravidic speaking people inhabiting the Indian peninsula. The 'Caucasoid share' in their gene pool is thought to be related predominantly to the Indo-European speakers. A commonly held hypothesis, albeit not the only one, suggests a massive Indo-Aryan invasion to India some 4,000 years ago [1]. Recent limited analysis of maternally inherited mitochondrial DNA (mtDNA) of Indian populations has been interpreted as supporting this concept [2] [3]. Here, this interpretation is questioned. We found an extensive deep late Pleistocene genetic link between contemporary Europeans and Indians, provided by the mtDNA haplogroup U, which encompasses roughly a fifth of mtDNA lineages of both populations. Our estimate for this split is close to the suggested time for the peopling of Asia and the first expansion of anatomically modern humans in Eurasia [4] [5] [6] [7] [8] and likely pre-dates their spread to Europe. Only a small fraction of the 'Caucasoid-specific' mtDNA lineages found in Indian populations can be ascribed to a relatively recent admixture.

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Ulnar-mammary syndrome (UMS) is a pleiotropic disorder affecting limb, apocrine-gland, tooth, hair, and genital development. Mutations that disrupt the DNA-binding domain of the T-box gene, TBX3, have been demonstrated to cause UMS. However, the 3' terminus of the open reading frame (ORF) of TBX3 was not identified, and mutations were detected in only two families with UMS. Furthermore, no substantial homology outside the T-box was found among TBX3 and its orthologues. The subsequent cloning of new TBX3 cDNAs allowed us to complete the characterization of TBX3 and to identify alternatively transcribed TBX3 transcripts, including one that interrupts the T-box. The complete ORF of TBX3 is predicted to encode a 723-residue protein, of which 255 amino acids are encoded by newly identified exons. Comparison of other T-box genes to TBX3 indicates regions of substantial homology outside the DNA-binding domain. Novel mutations have been found in all of eight newly reported families with UMS, including five mutations downstream of the region encoding the T-box. This suggests that a domain(s) outside the T-box is highly conserved and important for the function of TBX3. We found no obvious phenotypic differences between those who have missense mutations and those who have deletions or frameshifts.

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Purpose: To identify the gene causing tarsal/carpal coalition syndrome (TCC). Methods: Individuals from three kindreds with TCC and normal hearing were used to map TCC and screen for mutations in Noggin (NOG). Results: Three different missense mutations in NOG were found. Two of these mutations are identical to mutations previously reported to cause proximal symphalangism (SYM1). Conclusions: TCC is allelic to SYM1, and at least two different mutations in NOG can result in either TCC or SYM1 in different families. This finding suggests that phenotypic differences between these conditions are caused by epistatic modifiers of NOG. Genet Med 2001:3(5):349 -353. Key Words: tarsal/carpal coalition syndrome, symphalangism, NogginThe genetic analysis of human malformation syndromes characterized by disturbances of skeletal development provides important insights about the control of bone growth and maintenance. Tarsal/carpal coalition syndrome (TCC; OMIM 186570) is an autosomal dominant disorder characterized by fusion of the carpals, tarsals, and phalanges; short first metacarpals causing brachydactyly; and humeroradial fusion. 1,2 At birth, all affected individuals have stiffness of the proximal interphalangeal (PIP) joint of the 5th digit with or without bony synostosis. Over time, the distal end of the proximal phalanx and the proximal end of the middle phalanx fuse. As an individual ages, progressive fusion of the PIP joints of digits 4, 3, and 2 proceeds sequentially (Fig. 1). The distal interphalangeal joints are affected less commonly. Humeroradial fusion is not present in infancy but can be noted shortly thereafter. Abnormalities of the elbow are the most variable feature.The most substantial disabilities suffered by individuals with TCC are caused by the abnormalities of the ankle and foot. Often, ambulating is painful and difficult, necessitating palliative and/or corrective surgical intervention. Height, facial characteristics, and intelligence are normal. Penetrance of the gene appears to be complete, and the clinical findings are similar among males and females.We collected phenotypic data and biological materials from members of a family with TCC of the "Fuhrmann type" that had been previously reported by Drawbert et al. 2 An updated pedigree revealed that 17 individuals in this family (K1) are affected. Data were also collected from two additional unrelated families (K2 and K3) with TCC. METHODS Clinical evaluationAll studies were performed with the approval of the Institutional Review Board of the University of Utah and the General Counsel of the Shriners Hospitals for Children. After obtaining informed consent, each participant was evaluated by history and physical examination and/or review of medical records. Radiographs were performed on all individuals. Individuals in three unrelated families in which TCC was segregating in an autosomal dominant pattern were selected for linkage studies and mutation analysis. Twelve of 13 living affected individuals in family K1 and all 6 living affected individual...