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

Osma S. Rautila; Karri Kaivola; Harri Rautila; Laura Hokkanen; Jyrki Launes; Timo E. Strandberg; Hannu Laaksovirta; Johanna Palmio; Pentti J. Tienari

doi:10.1016/j.ajhg.2023.12.019

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

Osma S. Rautila^*
, Karri Kaivola
, Harri Rautila
, Laura Hokkanen
, Jyrki Launes
, Timo E. Strandberg
, Hannu Laaksovirta
, Johanna Palmio
, Pentti J. Tienari

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

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Abstract

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 subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18–20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18–20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based 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.

Original language	English
Pages (from-to)	383-392
Number of pages	10
Journal	American Journal of Human Genetics
Volume	111
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2023.12.019
Publication status	Published - Feb 2024
Publication type	A1 Journal article-refereed

Funding

This study was funded by the Finnish Cultural Foundation , Päivikki and Sakari Sohlberg Foundation , Paulo Foundation , the Sigrid Jusélius Foundation , Maire Taponen Foundation , the Finnish Brain Foundation , the Finnish Medical Foundation , the Biomedicum Helsinki Foundation , Helsinki University Hospital grants , ALS tuttu ry and the Finnish Academy ( 318868 ). We thank all the study participants for their generous participation in the ALS, PLASTICITY, DEBATE, and HBS studies. The data used for the research was phased with the THL Biobank's SISu v3 Imputation reference panel obtained from THL Biobank. We thank the Sequencing Informatics Team, FIMM Human Genomics, University of Helsinki, and the participants of the FINRISK, Health 2000, and Migraine Family studies for the work done in preparation of the reference panel data. Thank you to Dr. Joona Sarkkinen, Dr. Jani Huuhtanen, and Dr. Sofie Lundgren for information on Zenodo and other data sharing-related inquiries. This study was funded by the Finnish Cultural Foundation, Päivikki and Sakari Sohlberg Foundation, Paulo Foundation, the Sigrid Jusélius Foundation, Maire Taponen Foundation, the Finnish Brain Foundation, the Finnish Medical Foundation, the Biomedicum Helsinki Foundation, Helsinki University Hospital grants, ALS tuttu ry and the Finnish Academy (318868). P.J.T. holds a patent on C9orf72 in diagnostics and treatment of ALS/FTD.

Funders	Funder number
Finnish Brain Foundation
THL Biobank
Helsingin yliopisto
Helsingin ja Uudenmaan sairaanhoitopiiri
Suomen Lääketieteen Säätiö
Academy of Finland	318868
Suomen Kulttuurirahasto
Biomedicum Helsinki -säätiö
Päivikki ja Sakari Sohlbergin Säätiö
Sigrid Juséliuksen Säätiö
Paulon Säätiö
Maire Taposen Säätiö

Keywords

ALS
C9orf72
FTD
GGGGCC
haplotype sharing tree
HAPTK
HST
repeat disorders
repeat expansion

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2023.12.019Licence: CC BY

1-s2.0-S0002929723004512-mainFinal published version, 8.74 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202402162318Licence: CC BY

Cite this

Rautila, O. S., Kaivola, K., Rautila, H., Hokkanen, L., Launes, J., Strandberg, T. E., Laaksovirta, H., Palmio, J., & Tienari, P. J. (2024). The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK. American Journal of Human Genetics, 111(2), 383-392. https://doi.org/10.1016/j.ajhg.2023.12.019

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

abstract = "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 subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18{\textendash}20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18{\textendash}20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based 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.",

keywords = "ALS, C9orf72, FTD, GGGGCC, haplotype sharing tree, HAPTK, HST, repeat disorders, repeat expansion",

author = "Rautila, \{Osma S.\} and Karri Kaivola and Harri Rautila and Laura Hokkanen and Jyrki Launes and Strandberg, \{Timo E.\} and Hannu Laaksovirta and Johanna Palmio and Tienari, \{Pentti J.\}",

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doi = "10.1016/j.ajhg.2023.12.019",

language = "English",

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Rautila, OS, Kaivola, K, Rautila, H, Hokkanen, L, Launes, J, Strandberg, TE, Laaksovirta, H, Palmio, J & Tienari, PJ 2024, 'The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK', American Journal of Human Genetics, vol. 111, no. 2, pp. 383-392. https://doi.org/10.1016/j.ajhg.2023.12.019

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T1 - The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK

AU - Rautila, Osma S.

AU - Kaivola, Karri

AU - Rautila, Harri

AU - Hokkanen, Laura

AU - Launes, Jyrki

AU - Strandberg, Timo E.

AU - Laaksovirta, Hannu

AU - Palmio, Johanna

AU - Tienari, Pentti J.

PY - 2024/2

Y1 - 2024/2

N2 - 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 subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18–20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18–20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based 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.

AB - 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 subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18–20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18–20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based 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.

KW - ALS

KW - C9orf72

KW - FTD

KW - GGGGCC

KW - haplotype sharing tree

KW - HAPTK

KW - HST

KW - repeat disorders

KW - repeat expansion

U2 - 10.1016/j.ajhg.2023.12.019

DO - 10.1016/j.ajhg.2023.12.019

M3 - Article

C2 - 38242117

AN - SCOPUS:85183488292

SN - 0002-9297

VL - 111

SP - 383

EP - 392

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

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

Abstract

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Keywords

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ASJC Scopus subject areas

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