Jill Pecon Slattery, Ph.D.
Staff Scientist
[Biography] [Research] [Recent Publications]
{E-Mail Address} slattery@ncifcrf.gov
Research:
MOLECULAR
PHYLOGENETICS AND COMPARATIVE GENOME RESEARCH
OVERVIEW
Characterization of mutation processes within genes and
across genomes is fundamental to the research mission of the Laboratory of
Genomic Diversity (LGD) and is greatly facilitated by the field of molecular
phylogenetic analysis. In addition
to traditional applications in taxonomy and systematics, the following represent
some of our more novel applications of molecular phylogenetic methods involving:
1) genetic patterns in retroviral emergence and global dissemination and 2)
evolution of genes located on the mammalian sex chromosomes.
Summary of Published
Research
Retroviral Evolution
Our research is focused on three
major areas: 1) Human and simian forms of T-cell leukemia/lymphoma virus (HTLV/STLV);
2) lentiviruses closely related to human immunodeficiency virus (HIV)
which infect multiple species of cat (FIV) and species of non-human primates (SIV)
and 3) endogenous retroviruses incorporated into the cat genome.
With each of these projects, we define overall levels of genetic
diversity; specific rates of mutation within and between different regions of
the viral genome; relatedness among viral strains from geographically diverse
regions; and estimation of the pattern of divergence of the virus into extant
lineages.
Our research with HTLV/STLV strains
show that despite broad genomic similarities, type 1 and type 2 do not share
concordant evolutionary histories. HTLV-1/
STLV-1 strains are united by distinct phylogeographic patterns, infection of
over 20 primate species, multiple episodes of inter-species transmission, and
exhibit a range in levels of genetic divergence.
In contrast, type 2 viruses are isolated from only two species (Homo
sapiens and Pan paniscus) and are
paradoxically endemic to both Amerindian tribes of the New World and human Pygmy
villagers in Africa. Further,
HTLV-2 is spreading rapidly through new host populations of intravenous drug
users. Despite such clearly
disparate host populations, the resultant HTLV-2/STLV-2 phylogeny exhibits
little phylogeographic concordance and indicates low levels of transcontinental
genetic differentiation. Together,
these patterns generate a model of HTLV/STLV emergence marked by an ancient
ancestry, differential rates of divergence, and continued global expansion.
First described in domestic cat (Felis catus ) feline
immunodeficiency virus (FIV) is a lentivirus related to human immunodeficiency
virus (HIV). Like HIV, FIV causes
acquired immune deficiency syndrome (feline AIDS) in domestic cat by infecting T
lymphocytes and macrophages. Infected cats manifest symptoms, disease
progression and immune responses markedly similar to humans with HIV. However, the clear parallels between FIV in domestic cat and
HIV in humans are even more intriguing by the lack of discernable disease in 17
other cat species with antibodies that cross-react with FIV.
We have examined the genetic diversity of species-specific strains of FIV
from domestic cat, puma and lions. Our comprehensive genetic and phylogenetic
investigations reveal FIV isolated from the 3 species possess unique
evolutionary histories. Domestic cat FIV (FIV-Fca) phylogeny reflects a recent
evolutionary history, marked by the increased mobility of humans and their pets
in which three of the five recognized subtypes (or clades) are composed of
closely-related strains from cats dwelling on different continents.
In contrast, 22% of wild-caught pumas sampled throughout North and South
America are infected with a specifies-specific strain (FIV-Pco) that exhibits
large sequence divergence among 15 lineages.
The high level of genetic diversity, widespread distribution, and
distinct monophyly uniting the 15 deeply divergent lineages within FIV-Pco
isolates suggest a long period of evolution within puma.
Lion FIV (FIV-Ple) diverged into three distinct lineages separated by
large genetic distances comparable to those between FIV-Pco lineages, yet exists
within lions from the same localities. Most
likely, FIV-Ple has an ancient origin, and subsequently evolved into the three
major clades in populations of lions that were formerly apart, and now recently
converged, within east and south Africa.
Sex Chromosome Evolution
The eutherian Y chromosome is
unusual because conventional recombination with the X is limited to genes within
the small pseudoautosomal region (PAR). Comparative
analyses of mammalian sex chromosomes suggests that the Y acquires genes through
recombination with the X in the PAR, and that these genes subsequently undergo
extensive repositioning into the non-recombining region of the Y (NRY) via
inversion and intra-chromosomal translocation.
There, X-Y recombination ceases, and genes in the NRY are predicted to
either become specialized for male function or gradually degenerate from the
accumulation of deleterious mutations through processes such as Muller’s
ratchet hitchhiking with favorable mutations at other Y genes.
Using the cat family Felidae as a
reference phylogeny to define gene evolution, we have identified novel forms of
recombination, estimated exon and intron patterns of diversity, and identified
unique subfamilies of SINE retroelements on the sex chromosomes. Our
phylogenetic analyses of X-Y homologues, Zfx and Zfy, among 26 felid species
indicate two ancestral episodes of directed genetic exchange (ectopic gene
conversion) from X to Y: once
during the evolution of pallas cat and once in a common predecessor of ocelot
lineage species. Replacement of the
more rapidly evolving Y homologue with the evolutionarily constrained X copy may
represent a mechanism for adaptive editing of functional genes on the
non-recombining region of the mammalian Y-chromosome, background selection and
insertion of retroposons.
In addition, phylogenetic analysis of the terminal intron of
Zfy and Zfx in 34 felid species provides a robust estimation of male:female
substitution rate differences and thus, male-driven evolution. Zfy sequence
variation evolves at about twice the rate of Zfx and both gene intron sequences
accurately track feline hierarchical topologies. As homoplasies are infrequent
in patterns of nucleotide substitution, the Y chromosome sequence displays a
remarkable degree of phylogenetic consistency among cat species and provides a
highly informative glimpse of divergence of sex chromosome sequences in Felidae.
Correcting for the pattern of inheritance between Y and X chromosomes,
our estimate of am = 4.38 (95% confidence interval of 3.76 to 5.14) is
intermediate between that computed for rodents and primates, and consistent with
the hypothesis of male driven evolution. Further
investigation of sequence diversity of Y genes revealed unique subfamilies of
SINE inserts. Short interspersed
elements, SINEs, are forms of “selfish” DNA that exist in high copy number
scattered throughout eukaryotic genomes, and combined with long interspersed
nuclear elements (LINEs) and retro-elements resembling retroviruses, may
constitute 36% of the total genome. Research
on the human Alu SINE family and novel SINEs from other vertebrate and
invertebrate taxa suggest these forms of repetitive DNA may prove to be a
powerful, albeit controversial, tool in phylogenetic informatics.
Our research provides unique phylogenetic depictions of SINEs isolated
from intronic regions of three genes (Zfy, Ube1Y, and Smcy)
located in the NRY. Using
representative taxa from the carnivore order, we demonstrate the following: 1)
major SINE lineages exist specific to each carnivore family; 2) within carnivore
families, SINE retroposons provide cladistic markers of speciation but also, 3)
exhibit stochastic intra-species transposition ; and 4) homoplasy with identical
insertions in two species from distantly related lineages.