The Mueller laboratory explores the evolution and functions of structurally complex genomic regions and their associated genes in the germline. We use a combination of molecular and computational approaches to:

1. Better understand large (>10kb), nearly identical (>99% nucleotide identity), palindromic sequences on the mammalian X and Y chromosomes, where they are enriched, and on autosomes, where they are rare.

2. Learn how selfish genes harbored in complex genomic regions increase their own transmission to the next generation, via genetic and molecular analyses of germ cells in the mammalian testes and ovaries.

We aim to translate basic knowledge of these complex genomic regions and their associated genes into new understandings of human infertility, how genomes evolve, and how genes can disobey Mendelian inheritance.

X versus Y chromosome conflict

The X and Y chromosomes are a battleground for genes in conflict, each chromosome vying to gain a germline transmission advantage over the other. X- and Y-linked linked genes in conflict are more readily detectable, because they result in transmission distortion of male versus female offspring (sex ratio distortion). A few X- and Y-linked genes in conflict have been identified, but their mechanism for conferring a selective advantage is poorly understood. Our laboratory recently found that mice carrying deletions or duplications of a newly-acquired and highly duplicated X-linked gene family, Slxl1, distort the sex ratio. Slxl1, and its competitor, Sly, are thought to affect the fitness of an X- versus Y-bearing sperm via interanctions with other sex-linked genes. We believe that X- versus Y-linked gene conflict via dose-based mechanisms may be a universal phenomenon that is continually reshaping sex chromosome evolution. Our laboratory is currently studying the underlying mechanistic basis of this conflict in mice and the potential for co-amplified genes playing similar dose-dependent roles in other mammals.

Slxl1 versus Sly genetic conflict drives their co-amplification

Biology of Large Palindromes

One of the most distinctive characteristics of mammalian sex chromosomes is the presence of large palindromes (arrows, right, or tacocat in english): DNA sequences on one strand with matching sequence on the reverse complementary strand. Large (>10 kb) palindromic sequences are enriched on the mammalian X and Y chromosomes and harbor gene families (≥2 nearly-identical gene copies) expressed almost exclusively in spermatogenic cells. Due to the complexity, size, and repetitive nature of large sex chromosome palindromes, the roles of individual palindromic gene families in spermatogenesis and the importance of their genomic architecture as palindromes are poorly understood. We are exploring the biology of X-palindromes and their associated genes by examining their associated genes functions, the importance of their native genomic architecture, and their rapid molecular evolution.

Mouse X-ampliconic regions and representative palindromic genomic architecture