Four different forms of a non-receptor type proteintyrosine phosphatase are generated by alternative splicing; two of these forms (PTP-S2 and PTP-S4) are major forms, which are expressed in rat as well as human cells. Here we report that PTP-S2 binds to nonspecific DNA in vitro and localizes in the nucleus upon transfection in HeLa cells. PTP-S4 does not bind to nonspecific DNA and shows perinuclear and cytoplasmic localization. Removal of the C-terminal 34 amino acids of PTP-S4 gives rise to a truncated protein, which binds to nonspecific DNA and localizes to the nucleus. PTP-S4, but not PTP-S2, interacts strongly with the isolated nuclear matrix. The two forms of this tyrosine phosphatase show different substrate specificity in vitro, a feature novel to splice variants of tyrosine phosphatases. Mitogenic stimulation induces mRNAs for PTP-S2 as well as for PTP-S4 in the G 1 phase during liver regeneration. These results suggest that alternative splicing gives rise to two protein-tyrosine phosphatases with distinct substrate specificities and subcellular locations. The 34 amino acids at the C terminus of PTP-S4 play a critical role in determining substrate specificity, subcellular location, and interaction with nuclear matrix and DNA.

BackgroundHuman genetic diversity observed in Indian subcontinent is second only to that of Africa. This implies an early settlement and demographic growth soon after the first 'Out-of-Africa' dispersal of anatomically modern humans in Late Pleistocene. In contrast to this perspective, linguistic diversity in India has been thought to derive from more recent population movements and episodes of contact. With the exception of Dravidian, which origin and relatedness to other language phyla is obscure, all the language families in India can be linked to language families spoken in different regions of Eurasia. Mitochondrial DNA and Y chromosome evidence has supported largely local evolution of the genetic lineages of the majority of Dravidian and Indo-European speaking populations, but there is no consensus yet on the question of whether the Munda (Austro-Asiatic) speaking populations originated in India or derive from a relatively recent migration from further East.ResultsHere, we report the analysis of 35 novel complete mtDNA sequences from India which refine the structure of Indian-specific varieties of haplogroup R. Detailed analysis of haplogroup R7, coupled with a survey of ~12,000 mtDNAs from caste and tribal groups over the entire Indian subcontinent, reveals that one of its more recently derived branches (R7a1), is particularly frequent among Munda-speaking tribal groups. This branch is nested within diverse R7 lineages found among Dravidian and Indo-European speakers of India. We have inferred from this that a subset of Munda-speaking groups have acquired R7 relatively recently. Furthermore, we find that the distribution of R7a1 within the Munda-speakers is largely restricted to one of the sub-branches (Kherwari) of northern Munda languages. This evidence does not support the hypothesis that the Austro-Asiatic speakers are the primary source of the R7 variation. Statistical analyses suggest a significant correlation between genetic variation and geography, rather than between genes and languages.ConclusionOur high-resolution phylogeographic study, involving diverse linguistic groups in India, suggests that the high frequency of mtDNA haplogroup R7 among Munda speaking populations of India can be explained best by gene flow from linguistically different populations of Indian subcontinent. The conclusion is based on the observation that among Indo-Europeans, and particularly in Dravidians, the haplogroup is, despite its lower frequency, phylogenetically more divergent, while among the Munda speakers only one sub-clade of R7, i.e. R7a1, can be observed. It is noteworthy that though R7 is autochthonous to India, and arises from the root of hg R, its distribution and phylogeography in India is not uniform. This suggests the more ancient establishment of an autochthonous matrilineal genetic structure, and that isolation in the Pleistocene, lineage loss through drift, and endogamy of prehistoric and historic groups have greatly inhibited genetic homogenization and geographical uniformity.

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PTP-S is a widely expressed non-transmembrane protein tyrosine phosphatase (PTPase), which binds to DNA in vitro. The cellular PTP-S gene product is present mainly in the nucleus in association with chromatin. cDNAs related to PTP-S have been described from human and mouse cells. To establish the origin of molecular diversity in these cDNAs, genomic clones of rat PTP-S were isolated that span over 40 kb of the gene and contain 7 axons. The exon-intron splice sites in the catalytic domain are conserved between PTP-S and human PTP1B. Sequences specific to and homologous to human T-cell PTPase (TC-PTP) were found in the genomic clones of PTP-S, which are expressed in rat cells, as determined by using a specific probe and Northern blot analysis. Analysis of RNA from different rat tissues by reverse transcription-polymerase chain reaction (RT-PCR) showed the presence of four different forms of PTP-S mRNA (named PTP-S1, PTP-S2, PTP-S3, and PTP-S4). PTP-S1 is same as PTP-S reported previously by us. PTP-S2, which is the major form, differs from PTP-S1 in having additional 19 amino acids corresponding to exon E1. PTP-S4 is similar to human T-cell phosphatase. PTP-S3 differs from PTP-S4 in having a deletion of 19 amino acids corresponding to exon E1. Our results suggest that four different forms of PTP-S mRNA arise from a single gene by differential splicing. Two of these forms, PTP-S1 and PTP-S3, were not found in human cells, possibly due to the loss of an internal splice acceptor site in one of the exons, suggesting the occurrence of species-specific splicing in this gene.