A quantitative trait locus on chromosome 1 modulates intermale aggression in mice

Abstract

Aggression between male conspecifics is a complex social behavior that is likely modulated by multiple gene variants. In this study, the BXD recombinant inbred mouse strains (RIS) were used to map quantitative trait loci (QTLs) underlying behaviors associated with intermale aggression. Four hundred and fifty-seven males from 55 strains (including the parentals) were observed at an age of 13 ± 1 week in a resident-intruder test following 10 days of isolation. Attack latency was measured directly within a 10-minute time period and the test was repeated 24 hours later. The variables we analyzed were the proportion of attacking males in a given strain as well as the attack latency (on days 1 and 2, and both days combined). On day 1, 29% of males attacked, and this increased to 37% on day 2. Large strain differences were obtained for all measures of aggression, indicating substantial heritability (intraclass correlations 0.10-0.18). We identified a significant QTL on chromosome (Chr) 1 and suggestive QTLs on mouse Chrs 1 and 12 for both attack and latency variables. The significant Chr 1 locus maps to a gene-sparse region between 82 and 88.5 Mb with the C57BL/6J allele increasing aggression and explaining about 18% of the variance. The most likely candidate gene modulating this trait is Htr2b which encodes the serotonin 2B receptor and has been implicated in aggressive and impulsive behavior in mice, humans and other species.

Keywords: Ht2rb; aggression; anxiety; attack latency; impulsive behavior; mouse; recombinant inbred strains; resident-intruder; serotonin; social behavior.

Figure 1. Attack latencies on day 1

(A) BXD strain differences for attack latency day 1 (ordered by strain). (B) Whole genome QTL scan including all BXD strains. The x-axis represents chromosome number and megabase (Mb) position and the y-axis represents the likelihood ratio statistic (LRS) of linkage. Blue lines represent LRS across the genome. The pink and gray horizontal lines are approximate threshold values which are used to assess whether a peak is significant (P<0.05) or suggestive (P<0.63) respectively. Red lines indicate negative values (C57BL/6J alleles increasing trait values) and green lines indicate positive values (DBA/2J alleles increasing trait values). Gray lines are shown when the parental strain is unknown. The yellow bars represent the relative frequency of peak LRS at a given location from 2000 bootstrap resamples. (C) As B, but with five BXD strains (61, 65, 66, 89, 90) excluded.

Figure 2. Attack latencies on day 2

(A) BXD strain differences for attack latency on day 2 (ordered by strain). (B) Whole genome QTL scan including all BXD strains (see Figure 1 legend for description). (C) As B, but with five BXD strains (61, 65, 66, 89, 90) excluded.

Figure 3. Mean attack latencies on days 1 and 2

(A) BXD strain differences for mean attack latencies on days 1 and 2 (ordered by strain). (B) Whole genome QTL scan including all BXD strains (see Figure 1 legend for description). (C) As B, but with five BXD strains (61, 65, 66, 89, 90) excluded.

Figure 4. Proportion of males attacking on day 1

(A) BXD strain differences for proportion of males attacking on day 1 (ordered by strain). (B) Whole genome QTL scan including all BXD strains (see Figure 1 legend for description). (C) Whole genome QTL scan with five BXD strains (61, 65, 66, 89, 90) excluded.

Figure 5. Proportion of males attacking on day 2

(A) BXD strain differences for proportion of males attacking on day 2 (ordered by strain). (B) Whole genome QTL scan including all BXD strains (see Figure 1 legend for description). (C) As B, but with five BXD strains (61, 65, 66, 89, 90) excluded.

Figure 6. Proportion of males attacking at least once on days 1 and 2

(A) BXD strain differences for proportion of males attacking at least once on days 1 and 2 (ordered by strain). (B) Whole genome QTL scan including all BXD strains (see Figure 1 legend for description). (C) As B, but with five BXD strains (61, 65, 66, 89, 90) excluded.

Figure 7. Chromosome 1 and chromosome 12 interaction

(A) Whole genome QTL scan for attack latency day 2 excluding 6 BXD strains (B) Composite interval QTL scan suppressing the chromosome 1 QTL locus, rs13475957 (C) Composite interval QTL scan suppressing the chromosome 12 QTL locus, rs6346026.