Biomedical Engineering Reference
In-Depth Information
longtail macaques (such as those of the Philippines and
Mauritius). Major paraphyly has been reported within the
monophyletic clade of macaques belonging to the fas-
cicularis group of macaques. For example, Chinese rhesus
macaques are more similar to Japanese and Taiwanese
macaques than to their own con-specifics from India, and
longtail macaques from Indochina more closely resemble
rhesus macaques from China than their own con-specifics
in insular Southeast Asia, probably, due to inter-species
hybridization (
Kanthaswamy et al., 2008b
). Some have
called for a revision in the taxonomy of the fascicularis
group of macaque species to reflect this paraphyly and/or
hybridization (
Marmi et al., 2004
).
The low diversity in some longtail macaque populations
and high genetic subdivision among regional populations
undoubtedly result from founder effects, isolation from
gene flow, and genetic drift exacerbated by fluctuating
Pleistocene sea levels and dispersal in response to glacial
conditions.
Indian and Chinese rhesus macaques differ sufficiently
genetically that the two may provide optimal animal
models for the study of separate diseases and should be
regarded as members of separate subspecies. Some of these
genetic differences between rhesus macaques of different
geographical origins, and especially those in the Mhc
region, probably influence corresponding differences in
immune responses (
Geluck et al., 1993; Bontrop et al.,
1996; Baskin et al., 1997; Sauermann et al., 1997
). Asso-
ciations between Mhc alleles and immune responses that
have been reported are the consequence of different
patterns of T-cell activation resulting from differential
peptide binding by Mhc molecules with different combi-
nations of Mhc glycoproteins corresponding to different
combinations of Mhc alleles. Like some other regions of
the genome, the Mhc region is more variable in Chinese
than in Indian rhesus macaques (
Viray et al., 2001;
Doxiadis et al., 2003
). The high level of polymorphism of
several Mhc genes ensures an almost infinite number of
alternate T-cell repertoires in response to infection with
any given disease, and it is conceivable that a generally
broader repertoire provided by greater genetic heteroge-
neity at Mhc loci, as found especially in Chinese rhesus,
provides greater immunity to some infectious agents.
Correspondingly, phenotypic variance in treatment effects
during biomedical research on infectious diseases that
elicit immune responses can be minimized by using Indian
rhesus macaques, especially those with an Mamu-A*01
The recent observation that rhesus macaques of Chinese
origin are more resistant to infection with SIV than rhesus
of Indian origin (
Ling et al., 2002; Trichel et al., 2002
)
might reflect regional variation in the frequency or level of
heterogeneity of alleles at other loci that influence
susceptibility to SIV (albeit,
Burdo et al. (2005)
have
argued that this difference is due to adaptation of the
pathogen to passage in an Indian rhesus host). For example,
Indian rhesus macaques exhibit much lower copy numbers
of the CCL3L gene, a trait that accelerates the progression
of SIV in infected research subjects (
Degenhardt et al.,
2009
). The lower (approximately half) average copy
number of the CCL3L locus that encodes chemokine
ligands of CCR5, the principal co-receptor used by SIV/
HIV to enter cells, in Indian rhesus macaques than in
Chinese rhesus macaques accelerates their rate of
progression of SIV (
Degenhardt et al., 2009
). This locus
was estimated to contribute 18% of the variance in time to
progression to simian-AIDS. Thus, phenotypic variance
due to genetic contribution in SIV susceptibility can be
minimized and treatment effects more clearly resolved by
the use of research subjects, whether of Indian or Chinese
origin, with the same CNV of this gene. Together with
certain Mhc class I haplotypes that contribute 48% toward
variance in survival time of SIV-infected rhesus macaques
(
Sauermann et al., 2008
), this polymorphism contributes to
the marked difference betweeen the two regional pop-
ulations of rhesus macaques in their response to experi-
mental SIV infection.
Satkoski et al. (2011)
recently
reported statistically significant differences in linkage
disequilibrium between Indian and Chinese rhesus
macaques at the HIVEP3 (HIV type-1 enhancer binding
protein) that influences transcription of HIV-1. Thus, this
evidence of selection at this locus suggests that it might
also contribute to the different rates of progression of SIV
in Indian and Chinese rhesus macaques.
Other species of nonhuman primates commonly used in
biomedical research exhibit levels of genetic difference
equal to that exhibited by Indian and Chinese rhesus
macaques. Therefore, certain regional populations of
primate species or animals with specific genotypes that
influence phenotypic traits of interest and are particularly
common in those populations can provide more useful
animal models for the study of particular diseases than
other populations.
The recent completion of the draft sequence of the
rhesus genome (
Gibbs et al., 2007
) has facilitated the
discovery of single nucleotide polymorphisms (SNPs;
Ferguson et al., 2007; Hernandez et al., 2007; Malhi et al.,
2007; Satkoski et al., 2008b
), as well as ongoing efforts to
annotate the rhesus genome, the study of gene expression in
various tissues, and creation of a map of SNPs for use in
conducting linkage and association studies to identify
candidate genes for human disorders and their locations in
รพ
phenotype that reaches much higher frequencies in pop-
ulations of Indian than of Chinese rhesus macaques
(
Knapp et al., 1997
). Selecting only subjects for infectious
disease research with at least one Mamu A*01 allele
improves resolution of experimental treatment effects by
minimizing genetically determined differences in immune
responses.
