Genome Hunter

Jennifer A. Marshall Graves

(1941-present)

Australian evolutionary geneticist Jennifer Marshall Graves is a Distinguished Professor at La Trobe University (Melbourne), Professor Emeritus at the Australian National University (Canberra), Thinker-in-Residence at the University of Canberra, Fellow of the Australian Academy of Science, and L’Oreal-UNESCO Laureate. These recognitions are for her major contributions to the field of reproductive biology from studies on the origins of mammalian sex chromosomes and sex determining genes, to work on the organization and evolution of the mammalian genome. Her doctoral work at the University of California, Berkeley was on the control of DNA synthesis in mammal cells, but she was an early convert to comparative mapping and sequencing of genes in distantly related mammals. She proposed the first sequencing of marsupial and monotreme mammal genomes and directed the Centre for Kangaroo Genomics.

Over four decades Professor Graves’ has studied the evolution of sex determination through comparative studies of sex chromosomes in distantly related mammals and reptiles. Much of her work has focused on identifying differences between eutherian, marsupial, and monotreme mammals to trace the evolution of the mammalian genome and particularly of sex chromosomes. She found that the human XY chromosome pair contains an ancient region that is conserved between eutherians and marsupials (therian mammals), but eutherians have a region that was added more recently. This became critical when Professor Graves discovered that the first candidate for the sex determining gene lay in the new, rather than the old part of the Y – it was the wrong gene. This sparked a search for the right gene SRY, which was ultimately discovered by one of her graduates. SRY on the Y chromosome acts as a switch leading to the development of testes in an embryo, activating the key testis determining gene SOX9, an autosomal gene.

Professor Graves discovered that many regions were shared by the X and Y chromosomes, and by genome regions containing the same genes in other animals, implying that the mammalian X and Y descended from an ancestral autosome. She found that SRY has a partner SOX3 on the X chromosome with similar base sequence. SOX3, which is conserved in all animals, is therefore the ancestor of SRY.

Graves has studied animals that are generally considered strange, such as kangaroos and platypus, birds and lizards, in order to understand how sex, and sex chromosomes, evolved.  Although the genetic pathway that makes a testis is highly conserved, the switches that kick-start this process seem to have evolved independently in different lineages.

Platypus, one of the egg-laying monotreme mammals that separated very early from other mammals, have been especially instructive. Platypus sex chromosomes (there are 10!) share no homology with the therian XY pair; instead, the conserved therian X chromosome is homologous with a platypus autosome. This confirms that the therian X and Y chromosomes evolved from an ordinary chromosome in a common mammalian ancestor and places the origin of the therian X and Y chromosomes at the divergence of therians from monotremes 190 million years ago. Thus human sex chromosomes are much younger than we thought.

Graves’ also discovered other male-specific genes on the mammal Y with partners on the X, implying that these genes were located on the original autosome, but evolved a male-specific function. The few genes (45 in all) that remain on the Y are all that are left of an original 1000+ genes.  Professor Graves predicts that the process of loss of genes from the Y is ongoing, and the human Y will self-destruct in about 5 million years.

Professor Graves’ work has illuminated many of the mysteries of mammalian sex determination, and she is noted for identifying the male-determining Y chromosome as a degraded and mutated version of the X chromosome.

(Photo of JMG and joey by Micheline Pelletier GAMMA photo, used with permission)