Genes and gene families - Human Gene Evolution - page 188

The absence of introns in the IFNA and IFNB genes probably reflects the orga-
nization of the ancestral gene which could conceivably have been a retrotrans-
posed copy of an intron-containing interferon gene such as that encoding
interferon-

( IFNG ; 12q14) which contains three introns. The IFNA and IFNB
genes also exhibit an axis of internal symmetry, presumably the result of an inter-
nal duplication which must have occurred prior to the divergence of the two gene
families (Erickson et al ., 1984; Miyata et al ., 1985).

Nuclear receptor genes. Nuclear receptors are ligand-activated transcription
factors that regulate the expression of their target genes by binding to specific cis -
acting sequences in their promoter regions. This superfamily may be divided into
a minimum of three distinct groups, one containing the receptors for steroid hor-
mones (glucocorticoids, androgens, estrogens, progesterone, etc), a second con-
taining receptors for vitamin D, thyroid hormone and retinoic acid and a third
containing various 'orphan' receptors which putatively interact with ligands that
still remain to be identified. Nuclear receptors exhibit a modular organization
and contain at least four domains: an A/B domain involved in transactivation, a
highly conserved zinc finger-containing domain (C) involved in DNA binding, a
hinge (D) domain and a carboxy terminal (E) domain that is required for ligand
binding, dimerization and transcriptional regulation.
Human genes belonging to this superfamily include the androgen receptor
( AR ; Xq11-q12), estrogen receptor ( ESR1 ; 6q25), glucocorticoid receptor ( GRL ;
5q31), mineralocorticoid receptor ( MLR ; 4q31), progesterone receptor ( PGR ;
11q22), retinoic acid receptors ( RARA ; 17q21), ( RARB ; 3p24) and ( RARG ;

12q13), thyroid hormone receptors ( THRB ; 3p24) and

vitamin D receptor ( VDR ; 12q12-q14). Genes encoding the 'orphan' receptors
include hepatocyte nuclear factor 4 ( HNF4A ; 20q12-q13), the COUP transcrip-
tion factors ( TFCOUP1 , 5q14; TFCOUP2 ; 15q26), the retinoid X receptors
( RXRA , 9q34; RXRB , 6p21.3; RXRG , 1q22-q23) and the peroxisome prolifera-
tor-activated receptors

( THRA ; 17q21) and

( PPARD ;
6p21). It can be seen that the retinoic acid and thyroid hormone receptor genes
are arranged in two syntenic groups.
The ancestral nuclear receptor gene may have originated very early by fusion of
DNA-binding and steroid-binding domains (Amero et al ., 1992; Moore, 1990;
O'Malley, 1989). Indeed, Escriva et al . (1997) have proposed that the ancestral
nuclear receptor was an orphan receptor which subsequently acquired its ligand-
binding potential. Since numerous vertebrate nuclear receptors have Drosophila
homologues, the nuclear receptor superfamily must have diversified before the
divergence of arthropods and vertebrates more than 500 Myrs ago. This diversifi-
cation may have proceeded along the lines of the schema laid out in Figure 4.28 .
Two waves of gene duplication occurred, one very early on giving rise to the dif-
ferent receptor groups and a second in the vertebrate lineage. This was accompa-
nied by domain shuffling between genes (Escriva et al ., 1997; Laudet, 1997;
Laudet et al ., 1992). Sequence from the thyroid hormone receptor

( PPARA ; 22q12-q13), ( PPARG ) and

-related gene,
THRAL , appears to have been translocated to the THRA locus thereby creating
the final THRA exon. This must have occurred early on in mammalian evolution
since this organization is present in rat and human but not in chicken (Laudet et