Human Cytomegalovirus Genome - Human Cytomegalovirus - page 16

potential (Murphy et al. 2003a), and an abundant transcript coded in this region has
very recently been shown to function as an RNA (Reeves et al. 2007). Similarly, the
ORFs extending from UL107 to UL111 are not likely to encode proteins. Again,
the gene-finding algorithm found ORFs in this genome segment to have very low
coding potential, and the so-called 5-kb transcript, an intron that functions as an
RNA molecule (Kulesza and Shenk 2006), extends through this region. Finally, the
ORFs from UL58* through UL68* span a region that includes the HCMV ori Lyt.
Six of the ORFs in this region were tested by the gene-finding algorithm and
classed as unlikely to encode a protein. Collectively, these two RNA-coding regions
plus the ori Lyt domain are unlikely to contain protein-coding ORFs, removing all
or most of 26 ORFs in these regions from further consideration. This leaves 33
ORFs that are present in all five HCMV clinical isolates, but not in CCMV. They
are spread across the entire genome, although more are present in terminal domains;
they are generally relatively small, but not smaller than known protein-coding
ORFs; and some might encode segments that are incorporated into larger proteins
by splicing. The entire set are candidates for genes that are unique to the human
virus. CCMV likely contains several ORFs that are not present in human viruses
(Davison et al. 2003), so it is not surprising that human virus-specific ORFs would
also exist. In fact, one member of this set, UL111a, is known to encode a functional
IL10 homolog (Kotenko et al. 2000). Consequently, it is likely that additional ORFs
present in the human viruses but not CCMV will prove to encode proteins specific
to the human virus, but it will be necessary to test each for expression and/or func-
tion to be certain.
Genomic Organization: Evolution and Function
As is true for all herpes viruses, the HCMV genome contains a set of evolutionally
conserved, herpes virus-common ORFs that encode core functions required for
replication of the viral DNA and its assembly into virus particles (Mocarski et al.
2006). The 40 core HCMV genes are primarily located in the central region of the
viral genome within the U L domain. The terminal regions, including the U S
domain, contain genes that are cytomegalovirus-specific and generally nonessential
for replication in cultured cells. This organization leads to the view that modern
herpes viruses have evolved from a common ancestral virus by the acquisition of
specialized, luxury gene functions primarily within their terminal domains. This
generalization leads to the suggestion that the apparent noncoding region ranging
from RL2* through RL9* (Fig. 2) contains cytomegalovirus-specific functions.
Consistent with this prediction, the function of β2.7 RNA, which is coded in this
region, is without precedent in other herpes viruses. The RNA binds to mitochon-
drial enzyme complex I and blocks the induction of apoptosis in response to stress
(see the chapter by M. Reeves and J. Sinclair, this volume). Many additional genes
within the terminal regions, including much of the U S domain, have been shown
to function in immune evasion (see the chapter by C. Powers et al., this volume).