Biology subjects

Kaivola, K.

Publications and source records attributed to Kaivola, K..

3 recordsLinked to original sources

bioRxiv2026

Intergenerational instability of the C9orf72 hexanucleotide repeat

The C9orf72 hexanucleotide repeat expansion (HRE) is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It follows autosomal dominant inheritance in families, however, a high proportion of cases are sporadic, raising the possibility of parental premutation. We have demonstrated that intermediate-length alleles (IAs) with >18 repeats (allele frequency ~1%) belong to the same pool of haplotypes as the HRE, suggesting shared ancestry. Here, we tested whether alleles with >18 repeats expand in parental transmission. We used two repeat-primed PCR methods to analyze allele lengths in 539 genetically unselected parent-offspring pairs and in 152 pairs known to carry the SNP (rs139185008*C) that tags >18 repeat IAs and the HRE in Finland. We discovered intergenerational repeat length changes only in >20 repeat alleles. A significant (P = 0.0059) sex bias in 6-40 repeat alleles was noted using a logistic regression model. In this allele range, 12 out of 16 expansions were paternally inherited and 6 out of 7 contractions were maternally inherited. The expansion rate of 20-40 repeat alleles was 34 % in paternal and 11 % in maternal transmissions. In the 20-40 repeat range, most intergenerational expansions were 1-4 repeats in size (15/16), but one larger jump, a paternal expansion from 27 to 73 repeats, was observed. These results demonstrate that alleles with >20 repeats have an increased likelihood of instability, that a paternal expansion bias is observed in alleles with 20-40 repeats, and that expansion events are predominantly 1-4 repeats in size.

genetics↗

bioRxiv2026

Tracing the origin of Finnish gelsolin amyloidosis using haplotype sharing trees

Finnish gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant systemic amyloidosis caused by GSN c.640G>A p.D187N (rs121909715) founder variant. The disease was first described in 1969, and it was hypothesized that the Finnish patients share a common ancestor dating back to the 14th century. The link between two Finnish regions with high AGel incidence (Kanta-Hame and Kymenlaakso) has been hypothesized to have occurred in 1365 by a settler moving from Kanta-Hame to Kymenlaakso. Here, we used haplotype sharing tree (HST) to analyze Finnish AGel amyloidosis haplotypes to trace the geographic origin of the variant. We also estimated the time from the most recent common ancestor (MRCA) using single nucleotide polymorphism and short tandem repeat data. The HST -based analyses leveraging AGel amyloidosis cohorts from different Finnish geographic regions indicated, that the variant more likely appeared first in Kymenlaakso, not Kanta-Hame, contrary to the original hypothesis. The MRCA estimates for Finnish AGel ranged from 15 to 40 generations using four different methods, the mean of all estimates (27 generations) dated back to the 14th century. Thus, the data supports the original hypothesis on the variants spreading temporally, but not geographically. These results illustrate the use of HSTs in the analysis of haplotype structures and in tracing the ancestry of a founder variant.

genetics↗

bioRxiv2023

The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK

The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of cases are sporadic. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HST) with the novel haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE carriers and discovered that IAs containing [≥]18-20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA carriers, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.

genetics↗