A study of polymorphic endogenous retroviruses in humans: Implications in host health and genome evolution.
endogenous retroviruses (HERVs) result from the integration of retroviral DNA into
germline cells. The recently active human MMTV-like HML-2 group has been the focus of
this project. An analysis of the HML-2 group reveals their representation in the
published genome by ~90 full-length proviruses and ~1000 solitary-LTRs. The HML- 2
proviruses can be divided into three subgroups, ... read morebased on the phylogenetic comparison of
the paired LTRs belonging to each element, namely, the LTR5Hs, LTR5A, and LTR5B. The
analyses provide sequence-based and phylogenetic support that the LTR5B are the oldest
of the HML-2 proviruses, with a few shared sites in Old World monkeys. Also supported by
phylogenetic analysis and by estimated times of the activities of each subgroup, the
LTR5B subgroup is ancestral to both the LTR5A and LTR5-Hs. Only the LTR5-Hs have been
active in humans. Phylogenetic analyses indicate the evolutionary activities of the
LTR5-Hs have differed from that of the LTR5A and B subgroups, the latter two having
experienced increases in copy number as a direct result of association with segmental
duplication events within the host genome. Also we present the findings that the LTR5A
elements are associated with a specific group of genome segments, and are found in more
than half of the recently formed duplicons. The HML-2 group represents the only HERVs
with human-specific integrations, of which at least 11 HML-2 proviruses are polymorphic
in integration site and frequency within the population. The expression of HML-2
proviruses has been well reported to be up-regulated in a number of diseases. The
effects of HERV expression in human tissues are poorly understood, as is how HML-2
expression relates to a particular diseased state. In this respect, polymorphic
integrations have been given attention as they are conserved in sequence though present
in a fraction of the population. We used high resolution DNA hybridization from human
genomic DNAs in order to visually infer the distribution of newly formed and as-yet
uncharacterized polymorphic HML-2 proviruses. The case-control analyses of DNAs from two
human diseases revealed no statistical support for a genetic association of any `new'
polymorphic element with disease, and are consistent with previous studies of similar
approach. Nevertheless, we have provided evidence that as many as 15 polymorphic
proviruses are detected within human DNAs that vary in frequencies among the samples. We
observed a few present at quite low frequencies, for example in one or two of 120 tested
samples -below 1%, with regard to the samples analyzed, a far lower representation than
seen in any other polymorphic provirus. Such a provirus would be highly conserved and
might also exhibit retained functions.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Molecular Microbiology.
Advisor: John Coffin.
Committee: Carol Kumamoto, Katya Heldwein, Naomi Rosenberg, and Paul Bieniasz.
Keywords: Molecular biology, and Microbiology.read less
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