Topic Overview:

The majority of liver cells contain an abnormal number of chromosomes, but these cells still retain their ability to divide. Researchers have long puzzled over why liver cells have unusual chromosome numbers, a state known as aneuploidy, and whether this genetic variation provides some benefit. Duncan recently demonstrated that regenerating polyploid hepatocytes undergo specialized cell divisions to form aneuploid daughter cells, generating a high degree of genetic diversity within the liver.

To test whether aneuploidy protects liver cells against liver injury, Duncan’s lab examined a mouse model of liver disease caused by deficiency of fumarylacetoacetate hydrolase (Fah), using a strain of mice heterozygous for a mutation in the homogentisic acid dioxygenase (Hgd) gene located on chromosome 16.  Loss of the remaining Hgd allele protects from Fah deficiency.  When adult mice heterozygous for Hgd and lacking Fah were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. Array comparative genomic hybridization and metaphase karyotyping were performed to determine whether aneuploidy played a role in this phenomenon. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury.  This result indicates that selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury.  Active studies in Duncan’s lab involve elucidating mechanisms that control hepatic polyploidy and aneuploidy, as well as exploring how these processes affect human disease.