duperis a null mutation of Cryptochrome 1 in Syrian hamsters

Abstract

Significance We successfully identified the duper allele as a null mutation of Cryptochrome 1 in Syrian hamsters. Here, we have shown the use of fast homozygosity mapping as an effective approach to identify causal mutations in mammals, despite lacking chromosomal genome information. In the course of this work, we improved the draft Syrian hamster genome and generated datasets necessary to exploit Syrian hamsters as a modern genetic research model. The unique physiological features of Syrian hamsters make them a desirable model to investigate human diseases, including circadian disorders, cancer, heart function, metabolism, and infectious diseases (e.g., severe acute respiratory syndrome coronavirus 2).

The duper mutation reveals previously unsuspected functions of Cryptochrome 1 in circadian entrainment and heart disease

“…Results of our sequencing efforts revealed that duper mutant hamsters are Cry1 -null ( 12 ). Effects of Cry1 deletion on latency to shift entrained phase have not been reported in mice.…”

“…We discovered duper, a recessive mutation that shortens the circadian period (τ DD ) of Syrian hamsters to 22.8 h and amplifies the PRC ( 9 – 11 ). Using a forward genetic strategy, we crossed the duper allele into the cardiomyopathic Bio14.6 strain and used fast homozygosity mapping to determine that these mutants are deficient in Cryptochrome 1 ( Cry1 ), a powerful repressor of transcriptional activation by BMAL1:CLOCK heterodimers at E-box motifs ( 12 ).…”

“…Frequent phase shifts shorten the lifespan of hamsters that suffer from cardiomyopathy due to deletion of delta sarcoglycan ( dsg ; 15 , 16 ). We utilized the dsg -deficient Bio14.6 strain as the distant ecotype in our mapping studies ( 12 ). This also provided us with the opportunity to examine the impact of the duper mutation on longevity in cardiomyopathic hamsters.…”

Circadian Responses to Light in the BTBR Mouse

“…Mutations in other closely related enzymes such as mCK1ε, hCK1δ , and hPer2 also accelerate degradation of PER and shorten the circadian period ( Camacho et al, 2001 ; Akashi et al, 2002 ; Dey et al, 2005 ; Eide et al, 2005 ; Xu et al, 2005 ; Gallego and Virshup, 2007 ; Meng et al, 2008 ; Etchegaray et al, 2009 ; Lee et al, 2009 ; Walton et al, 2009 ). The spontaneous duper mutation observed in hamsters also shortens the circadian period ( Monecke et al, 2011 ) and has recently been linked to a mutation in the cry1 gene ( Lee et al, 2022 ). A similar short period mutant mouse, part-time (FRP = 21.4 h), discovered on a mutagenesis screen using BTBR mice, was also mapped to a loss of function of the cry1 gene ( Siepka et al, 2007 ).…”

“…Period mutants (animals with mutations that affect the FRP) have been valuable in understanding these interactions and understanding how properties of the clock interact with each other and ultimately determine an organism’s circadian adaptation to the environment around it. In some cases, these mutations target core clock genes that are integral components of the TTFL ( Ralph and Menaker, 1988 ; van der Horst et al, 1999 ; Cermakian et al, 2001 ; Lee et al, 2022 ) while in other cases the mutation affects neuropeptide signaling that likely couples the cell-autonomous oscillators ( Harmar et al, 2002 ; Colwell et al, 2003 ). The circadian behavior in these animals can ultimately inform us of the reasons for a lack of alignment with external cycles or an inability to respond to time cues that results from altered light schedules, aging, or disease.…”