Transcript SRY Gene on Chromosome Y Jon Scales Genetics Fall 2012

SRY Gene on Chromosome Y
Jon Scales Genetics Fall 2012
PAR
Introduction
SRY
Yp11 3
SRY is encodes a transcription of the HMG-box family. SRY
regulates male sexual development in mammals as shown in
the pathway in Figure 2. Mutations in SRY are known to cause
the condition gonadal dysgenesis. Persons with this condition
are phenotypically female, but do not express female
secondary sex characteristics.
PAR
Identification of SRY
Figure 1. SRY is located at Yp11.3
just outside the pseudoautosomal
region (PAR) of homology with the X
chromosome. The SRY gene is located at physical position 2654900 2655000 bp and consists of a single
exon.
Initially DNA from XX karyotype males was used to identify the
breakpoints of Y chromosome sequences translocated onto the
X chromosome. Once this region of the Y chromosome was
identified, large regions of 10-25 Kbp were inserted into
bacteriophage vectors. A region of Y-specific DNA near the
boundary of the pseudoautosomal region was found to detect
Y-specific sequences in several species of mammals. This
2.1Kbp fragment of DNA also detected an mRNA transcript in
testis but not other tissues.
1 GTAACAAAGAATCTGGTAGAAGTGAGTTTTGGATAGTAAAATAAGTTTCGAACTCTGGCA
61 CCTTTCAATTTTGTCGCACTCTCCTTGTTTTTGACAATGCAATCATATGCTTCTGCTATG
M Q S Y A S A M
121 TTAAGCGTATTCAACAGCGATGATTACAGTCCAGCTGTGCAAGAGAATATTCCCGCTCTC
9 L S V F N S D D Y S P A V Q E N I P A L
181 CGGAGAAGCTCTTCCTTCCTTTGCACTGAAAGCTGTAACTCTAAGTATCAGTGTGAAACG
29 R R S S S F L C T E S C N S K Y Q C E T
241 GGAGAAAACAGTAAAGGCAACGTCCAGGATAGAGTGAAGCGACCCATGAACGCATTCATC
49 G E N S K G N V Q D R V K R P M N A F I
301 GTGTGGTCTCGCGATCAGAGGCGCAAGATGGCTCTAGAGAATCCCAGAATGCGAAACTCA
69 V W S R D Q R R K M A L E N P R M R N S
361 GAGATCAGCAAGCAGCTGGGATACCAGTGGAAAATGCTTACTGAAGCCGAAAAATGGCCA
89 E I S K Q L G Y Q W K M L T E A E K W P
421 TTCTTCCAGGAGGCACAGAAATTACAGGCCATGCACAGAGAGAAATACCCGAATTATAAG
109 F F Q E A Q K L Q A M H R E K Y P N Y K
481 TATCGACCTCGTCGGAAGGCGAAGATGCTGCCGAAGAATTGCAGTTTGCTTCCCGCAGAT
129 Y R P R R K A K M L P K N C S L L P A D
541 CCCGCTTCGGTACTCTGCAGCGAAGTGCAACTGGACAACAGGTTGTACAGGGATGACTGT
149 P A S V L C S E V Q L D N R L Y R D D C
Expression of SRY
601 ACGAAAGCCACACACTCAAGAATGGAGCACCAGCTAGGCCACTTACCGCCCATCAACGCA
169 T K A T H S R M E H Q L G H L P P I N A
SRY is expressed in a variety of tissues. During embryogenesis,
it is expressed in the somatic cells of the genital ridge. In
adults, expression is detected in the germ cells in the testis.
661 GCCAGCTCACCGCAGCAACGGGACCGCTACAGCCACTGGACAAAGCTGTAGGACAATCGG
189 A S S P Q Q R D R Y S H W T K L *
Figure 3. SRY encodes a 845nt mRNA with an ORF of 615 bp
(including stop) from nt 96-711 which encodes a 204aa
protein. The SRY protein belongs to the HMG-box family of
DNA binding proteins. Them amino acids comprising the
HMG box (67-119) are indicated in red. The HMG box is
shared among numerous proteins which are members of the
SOX (SRY-box) family.
Figure 2. SRY sets in
motion a chain of gene
activations which give
rise to male sexual
development and simultaneously block the
development of female
reproductive structures.
.
Figure 4. There are homologs of SRY in all mammals. Here the
schematic human and mouse proteins are aligned by their HMG
boxes which are 89% identical. The mouse protein has a large
region of glutamine repeats that is apparently dispensable as
there is a nonsense mutation at the position of the asterisk in
one strain which cause does not affect sexual differentiation.
721 GTAACATTGGCTACAAAGACCTACCTAGATGCTCCTTTTTACGATAACTTACAGCCCTCA
781 CTTTCTTATGTTTAGTTTCAATATTGTTTTCTTTTCTCTGGCTAATAAAGGCCTTATTCA
841 TTTCA
Figure 5. HMG-box containing
transcription factors bind in the
minor groove of the DNA
double helix (pink). Binding in
the minor groove induces a
bend in the DNA. The HMG-box
sequences form a series of 3
alpha helices (shown in green).
Figure 6. Mutations known to cause gonadal dysgenesis are
indicated here. Note that the vast majority of these
mutations occur within the HMG box which is the DNA
binding domain of the protein.