A matter of life or death: How microsatellites emerge in and vanish from the human genome

Abstract

Microsatellites-tandem repeats of short DNA motifs-are abundant in the human genome and have high mutation rates. While microsatellite instability is implicated in numerous genetic diseases, the molecular processes involved in their emergence and disappearance are still not well understood. Microsatellites are hypothesized to follow a life cycle, wherein they are born and expand into adulthood, until their degradation and death. Here we identified microsatellite births/deaths in human, chimpanzee, and orangutan genomes, using macaque and marmoset as outgroups. We inferred mutations causing births/deaths based on parsimony, and investigated local genomic environments affecting them. We also studied birth/death patterns within transposable elements (Alus and L1s), coding regions, and disease-associated loci. We observed that substitutions were the predominant cause for births of short microsatellites, while insertions and deletions were important for births of longer microsatellites. Substitutions were the cause for deaths of microsatellites of virtually all lengths. AT-rich L1 sequences exhibited elevated frequency of births/deaths over their entire length, while GC-rich Alus only in their 39 poly(A) tails and middle A-stretches, with differences depending on transposable element integration timing. Births/deaths were strongly selected against in coding regions. Births/deaths occurred in genomic regions with high substitution rates, protomicrosatellite content, and L1 density, but low GC content and Alu density.

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

“…Alu sequences are composed of two long A-rich stretches frequently containing mononucleotide microsatellites (Arcot et al 1995;Kelkar et al 2011). Mononucleotide A/T repeats cause pausing of replicative DNA polymerases in vitro (Shah et al 2010) and, thus, may contribute to replication difficulties within aCFSs.…”

“…Mechanistically, Alu repeats have been studied extensively for their effect on nonhomologous recombination, which might impact chromosome stability (Cordaux and Batzer 2009;Konkel and Batzer 2010). Most alu repeats contain mononucleotide microsatellites (Arcot et al 1995;Kelkar et al 2011) which are involved in replication slippage, unequal crossing over, secondary structure formation, and DNA polymerase inhibition (Bhargava and Fuentes 2009;Shah et al 2010). Therefore, a role for mononucleotide microsatellites in genomic instability is well supported.…”

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

“…One can speculate that these different size requirements for pathology are related to the specific gene context and localization in genomic elements. 40 Nevertheless, given the bias toward increased (ATTTC) n size upon transmission, larger alleles might be expected to appear in affected individuals from other families with this repeat insertion. Notably, alleles of 280-850 units show reduced penetrance in SCA10, and alleles of 33-280 repeats have not been observed.…”

“…14,46-48 These A-rich tracts can be the basis for nucleotide substitution leading to microsatellite birth either through errors introduced during Alu reverse transcription or through the accumulation of mutations in Alu poly-A stretches after insertion. 40 This is the second neurodegenerative disease (in addition to SCA31) caused by an insertion in a polymorphic repeat located in an A-rich region of an Alu element. 14 In both cases, the insertion of the pathogenic repeat is flanked by ATTTT/AAAAT tracts, creating a large unstable repeat that shares similarities with expanded repeats.…”

Tandem repeat variation in human and great ape populations and its impact on gene expression divergence

“…Past technical constraints, however, limited the number of TRs that could be easily genotyped. For this reason, most TRbased studies of human diversity and intraspecies genetic divergence were restricted (Rosenberg et al 2002;Molla et al 2009;Pemberton et al 2009Pemberton et al , 2013Tishkoff et al 2009;Sun et al 2012) or focused on comparing reference genomes (Webster et al 2002;Kelkar et al 2008Kelkar et al , 2011Payseur et al 2011;Loire et al 2013). However, recent advances in sequencing methodology (for review, see Mardis 2008;Metzker 2010) and the development of novel software that can systematically genotype repeats at a genome-wide scale (for review, see Lim et al 2012) have permitted analysis of several thousand loci from multiple individuals in a cost-effective manner (McIver et al 2011(McIver et al , 2013Willems et al 2014).…”