Technical interview guide

Genome Assembly & Sequencing Technologies

How raw sequencing reads become a genome — short-read vs. long-read platforms, de Bruijn graph assembly, and what coverage actually buys you.

Read: 49 min
Practice MCQs: 25
Interview QA: 25
Edition: v3
Editorial status: Reviewed
Relevant for: Computational Biologist

Scope: Foundational Lander-Waterman and de Bruijn graph models; SPAdes, Canu, Flye, hifiasm, QUAST and BUSCO source publications; current Illumina, PacBio, Oxford Nanopore and NCBI guidance reviewed 2026-09-04.

Interview QA

Treat each question like a live interview question: answer out loud first (structure, assumptions, tradeoffs), then open the model answer to spot gaps and rehearse a tighter follow-up.

Curated: 2026-10-05 · Written: 2026-10-05 · Reviewed: 2026-10-04

QA-1

Design sequencing for a repeat-rich diploid genome.

QA-2

Assemble a small genome from paired short reads.

QA-3

Choose between raw long reads and HiFi reads.

QA-4

Set and audit an assembly coverage target.

QA-5

Distinguish error branches from biological variation.

QA-6

Explain repeat handling in an OLC assembler.

QA-7

Construct a small de Bruijn assembly graph.

QA-8

Select k-mer sizes for short-read assembly.

QA-9

Assess repeat resolvability before assembly.

QA-10

How do you use Hi-C contact maps and long reads to resolve chromosome-scale scaffolding and detect structural misassemblies?

QA-11

Set conservative graph-cleaning rules.

QA-12

How do you detect, separate, and screen out organellar DNA and cross-species contamination from high-coverage long-read de novo assemblies?

QA-13

Design a long-read polishing workflow.

QA-14

Choose a diploid assembly representation.

QA-15

Distinguish allelic and error bubbles.

QA-16

How do you detect and resolve phase-switch errors and chimeric contigs in diploid long-read de novo assemblies using trio-binning or Hi-C contact maps?

QA-17

Compare assemblies without misusing N50.

QA-18

Use NG50 in an assembly benchmark.

QA-19

Validate suspected structural errors.

QA-20

Interpret a BUSCO report for a diploid assembly.

QA-21

Create read-back assembly diagnostics.

QA-22

Validate and normalize a circular bacterial chromosome.

QA-23

Plan a metagenomic assembly.

QA-24

How do you reconstruct high-identity segmental duplications and alpha-satellite centromeric arrays that fail standard string-graph or de Bruijn graph resolution?

QA-25