Biology Reference
In-Depth Information
CLASS III
Class III resides in between class I and II, and is now known to be the most
gene-dense region of the entire human genome
[27,28]
. Importantly, the
class III region displays strong positive LD with HLA class I loci to its telo-
mere and with class II loci to its centromere; this LD is what character-
izes the highly conserved “ancestral” haplotypes that have been defined
in many human populations
[29]
. The class III region harbors genes that
participate in the stress response, several of which have been found to
influence risk of graft-versus-host disease (GVHD) after allogeneic trans-
plantation
[30-32]
.
Nomenclature
The application of DNA-based methods for typing HLA genes has resulted
in the discovery of novel alleles at an extraordinary rate
[7,8]
. To accom-
modate new sequence information, HLA nomenclature was recently
modified using a naming system that offers unlimited numerical digits.
The nomenclature captures four properties of sequences, in the following
order: the serological equivalent of the allele, the unique sequence that
gives rise to the unique protein, synonymous (silent) substitutions, and
level of expression of the molecule. Each of these four characteristics is
delimited by a colon ( : ). Using HLA-A*02:101:01:02N as an example, this
name provides information on the serological specificity (02), the unique
sequence
[101]
, the synonymous substitution (01) and the null allele
(02N). Additional letter suffixes denote proteins whose expression is
l
ow
(L),
s
oluble (S),
a
berrant (A), or whose product is
c
ytoplasmic (C), or of
q
uestionable expression (Q).
24
LD AND HAPLOTYPES
A hallmark of the MHC is its long-range positive LD, a mathematical
measurement of two or more markers that have a higher observed fre-
quency than would be predicted by their individual allele frequencies
[33,34]
. LD across the MHC demonstrates that occurrence of HLA tis-
sue types is not random
[29]
. Linked HLA genes are inherited from each
parent as a haplotype in classical Mendelian fashion. “Ancestral” hap-
lotypes represent highly conserved HLA-A, B, DR haplotypes that dis-
play conservation for “blocks” or stretches of sequences in the class I,
III and II regions
[29]
. In disease mapping, haplotypes serve as proxies
for ungenotyped markers because haplotypes define not one but many
physically linked markers.
In hematopoietic cell transplantation from unrelated donors, LD can both
help and hinder the identification of suitable donors. In general, the prob-
ability of identifying an HLA-matched donor is higher when the patient and
donor share a similar ethnic background
[35-38]
. When high LD exists, such
as with the HLA-A1, B8, DR3 haplotype, the probability of finding donors
with the same genotype is very high; when a patient has inherited a mater-
nal or paternal recombination event, however, LD is disrupted, and the like-
lihood of identifying matched donors will then depend on the frequency of
those alleles and antigens in the donor pool.
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