Hair-greying and melanocytic regulation of BCL2 in a non-model organism

Project Summary/Abstract
Hair-greying is an early and visible sign of aging with important psychosocial, commercial, and biologic
implications. The underlying mechanisms of hair-greying are not well-understood, but the anti-apoptotic BCL2
gene is thought to play a key role in this process.
Recent and unpublished studies from our group reveal that the “glacier” bear, a rare color variant of the
American black bear found in Southeast Alaska, is a natural model of hair greying that is likely caused by a
BCL2 mutation. Glacier bears exhibit variable degrees of hair-greying that occasionally spares the facial region
and distal limbs, and is histologically similar to human hair-greying. Genomic studies and genetic association
analysis have identified a single region on what corresponds to human chromosome 18 that contains 3 genes,
including BCL2. There are no protein-coding alterations in any of the 3 genes but there are 562 non-coding
variants within the candidate region, many of which lie in cis-regulatory elements (CREs).
In laboratory mice, loss-of-function for Bcl2 has pleiotropic consequences including small size, disruption of
kidney and lymphoid development, and postnatal lethality. These abnormalities have not been described in
glacier bears, leading us to hypothesize that the cause of hair-greying is disruption of a melanocyte-specific
regulatory element. To better understand the pathophysiology of hair-greying and regulation of BCL2, we will:
(1) Carry out additional genetic and histologic studies of glacier bear DNA and skin; and
(2) Apply a massively parallel reporter assay in three human cell lines to identify CREs for BCL2 and to identify
causative variants for the glacier bear mutation.

Grant Number: 5R21AG089946-02
NIH Institute/Center: NIH
Principal Investigator: Gregory Barsh