Counting unique molecular identifiers in sequencing using a multi-type branching process with immigration

DOI10.1016/J.JTBI.2022.111365MaRDI QIDQ2109343zbMATH OpenOpenAlexFDO

Authors S. Sagitov, Anders Ståhlberg

Publication date 20 December 2022

Published in Journal of Theoretical Biology (Search for Journal in Brave)

Copyright license Creative Commons Attribution 4.0 International

Full work available at URL https://arxiv.org/abs/2205.06405

zbMATH Keywords

growing immigrationPCR amplification ratePCR branching processsequencingtree-bookkeepingunique molecular identifier

Mathematics Subject Classification ID

Protein sequences, DNA sequences (92D20)

Abstract: Detection of extremely rare variant alleles, such as tumour DNA, within a complex mixture of DNA molecules is experimentally challenging due to sequencing errors. Barcoding of target DNA molecules in library construction for next-generation sequencing provides a way to identify and bioinformatically remove polymerase induced errors. During the barcoding procedure involving $t$ consecutive PCR cycles, the DNA molecules become barcoded by unique molecular identifiers (UMI). Different library construction protocols utilise different values of $t$. The effect of a larger $t$ and imperfect PCR amplifications is poorly described. This paper proposes a branching process with growing immigration as a model describing the random outcome of $t$ cycles of PCR barcoding. Our model discriminates between five different amplification rates $r_1$, $r_2$, $r_3$, $r_4$, $r$ for different types of molecules associated with the PCR barcoding procedure. We study this model by focussing on $C_t$, the number of clusters of molecules sharing the same UMI, as well as $C_t(m)$, the number of UMI clusters of size $m$. Our main finding is a remarkable asymptotic pattern valid for moderately large $t$. It turns out that $E(C_t(m))/E(C_t)approx{2}^{-m}$ for $m=1,2,ldots$, regardless of the underlying parameters $(r_1,r_2,r_3,r_4,r)$. The knowledge of the quantities $C_t$ and $C_t(m)$ as functions of the experimental parameters $t$ and $(r_1,r_2,r_3,r_4,r)$ will help the users to draw more adequate conclusions from the outcomes of different sequencing protocols.

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Cites work

• Branching Processes
• Branching processes in biology
• Estimation of the reaction efficiency in polymerase chain reaction
• Homogeneous branching processes with non-homogeneous immigration
• scientific article; zbMATH DE number 3349139 (Why is no real title available?)
• Random variation and concentration effects in PCR
• The structure of the allelic partition of the total population for Galton-Watson processes with neutral mutations

Cited in

(3)

• Error analysis of deep sequencing of phage libraries: peptides censored in sequencing
• scientific article; zbMATH DE number 6271723 (Why is no real title available?)
• Diffusion approximation of critical controlled multi-type branching processes

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