Chromosomal inversions between human and chimpanzee lineages caused by retrotransposons

Abstract

The long interspersed element-1 (LINE-1 or L1) and Alu elements are the most abundant mobile elements comprising 21% and 11% of the human genome, respectively. Since the divergence of human and chimpanzee lineages, these elements have vigorously created chromosomal rearrangements causing genomic difference between humans and chimpanzees by either increasing or decreasing the size of genome. Here, we report an exotic mechanism, retrotransposon recombination-mediated inversion (RRMI), that usually does not alter the amount of genomic material present. Through the comparison of the human and chimpanzee draft genome sequences, we identified 252 inversions whose respective inversion junctions can clearly be characterized. Our results suggest that L1 and Alu elements cause chromosomal inversions by either forming a secondary structure or providing a fragile site for double-strand breaks. The detailed analysis of the inversion breakpoints showed that L1 and Alu elements are responsible for at least 44% of the 252 inversion loci between human and chimpanzee lineages, including 49 RRMI loci. Among them, three RRMI loci inverted exonic regions in known genes, which implicates this mechanism in generating the genomic and phenotypic differences between human and chimpanzee lineages. This study is the first comprehensive analysis of mobile element bases inversion breakpoints between human and chimpanzee lineages, and highlights their role in primate genome evolution.

Figure 1. The 252 inversion loci between the human and chimpanzee lineages.

Blue and red circles indicate Alu-RMI and L1-RMI events, respectively. All inversions except for those caused by RRMI are indicated by green circles. The karyotype images were created using the idiographica webtool .

Figure 2. Sequence alignment of one recombined Alu element and two prerecombined Alu elements involved in an Alu-RMI event.

The recombined (chimeric) Alu element and two prerecombined Alu elements that contributed to its formation are showed in order. Identical nucleotides shared among elements are indicated by dots. Otherwise, differences are shown with letters. The recombination breakpoint for this event is located in the yellow box.

Figure 3. Alu and L1 subfamilies involved in RRMI events.

The proportion of Alu elements involved in Alu-RMI events (blue bars) and the proportion of Alu elements in each subfamily (black bars) are compared in the left side. The proportion of LINEs involved in L1-RMI events (red bars) and the proportion of L1 elements in each subfamily (gray bars) are compared in the right side.

Figure 4. Analysis of GC content in flanking regions of RRMI loci.

The vertical axis represents the relative frequency of RRMI loci within each GC bin. Black bars and blue bars indicate Alu-RMD and L1-RMD events, respectively.

Figure 5. RRMI between human and chimpanzee lineages.

The mechanism underlying RRMI is shown at the left. In the illustration of the ancestral state, the two retrotransposons have intact TSDs whose sequence is listed in the colored boxes. The shape “X” indicates recombination between the retrotransposons. In the illustration of the human-specific inversion, both retrotransposons are chimeric, and no longer have matching TSDs. For both illustrations, two arrows indicate the positions where each oligonucleotide primer anneals to for PCR amplification. Agarose-gel chromatographs of PCR products are shown on the right. The upper gel picture displays the ancestral state of the RRMI, while the lower gel picture displays the human-specific inversion. The DNA templates used in each PCR reaction are shown on top of the gel pictures.