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RNA-seq Preprocessing Pipeline using HISAT2

Project Overview

This project demonstrates a complete RNA-seq preprocessing workflow using publicly available sequencing data. The pipeline starts from raw paired-end FASTQ files and performs quality control, read trimming, genome alignment, BAM processing, and gene-level quantification.

The workflow was implemented on Ubuntu (WSL2) using widely adopted bioinformatics tools and follows best practices for RNA-seq preprocessing.


Workflow

Raw FASTQ Files
        │
        ▼
Quality Control (FastQC)
        │
        ▼
Read Trimming (fastp)
        │
        ▼
Genome Alignment (HISAT2)
        │
        ▼
SAM to BAM Conversion (SAMtools)
        │
        ▼
Sorting & Indexing BAM (SAMtools)
        │
        ▼
Gene Quantification (featureCounts)

Tools Used

Tool Purpose
Linux (Ubuntu WSL2) Bioinformatics environment
SRA Toolkit Download sequencing data
FastQC Raw read quality assessment
MultiQC Aggregate quality reports
fastp Adapter removal and quality trimming
HISAT2 RNA-seq read alignment
SAMtools BAM file processing
featureCounts Gene-level read counting

Software Versions

  • Ubuntu 24.04 (WSL2)
  • HISAT2
  • SAMtools
  • FastQC
  • MultiQC
  • fastp
  • featureCounts (Subread)

Project Structure

RNAseq-Cancer-Pipeline/
│
├── alignment/
├── bam/
├── counts/
├── figures/
├── qc/
├── raw_data/
├── reference/
├── results/
├── scripts/
├── trimmed_reads/
├── README.md
└── .gitignore

Input Data

  • Public paired-end RNA-seq FASTQ files
  • Human reference genome (GRCh38)
  • Gene annotation (GTF)

Pipeline Steps

1. Download RNA-seq Data

Sequencing reads were downloaded using the SRA Toolkit.


2. Quality Assessment

Raw sequencing quality was evaluated using FastQC.

Outputs:

  • HTML reports
  • ZIP reports

3. Read Trimming

Low-quality bases and adapter sequences were removed using fastp.

Outputs:

  • Trimmed FASTQ files
  • HTML report
  • JSON report

4. Genome Alignment

Trimmed reads were aligned against the Human GRCh38 reference genome using HISAT2.

Output:

  • SAM alignment file

5. BAM Processing

SAMtools was used to:

  • Convert SAM → BAM
  • Sort BAM
  • Index BAM

Outputs:

  • Sorted BAM
  • BAM Index (.bai)

6. Gene Quantification

featureCounts assigned aligned reads to annotated genes.

Outputs:

  • gene_counts.txt
  • gene_counts.txt.summary

Alignment Statistics

Metric Result
Total Reads 16,249,153
Overall Mapping Rate 91.95%
Primary Mapping Rate 90.63%
Properly Paired Reads 83.95%

The high mapping rate indicates successful alignment against the human reference genome.


Output Files

  • Sorted BAM file
  • BAM index
  • Gene count matrix
  • FastQC reports
  • fastp reports
  • Alignment statistics

Skills Demonstrated

  • Linux command line
  • Bash scripting
  • RNA-seq preprocessing
  • FASTQ quality assessment
  • Adapter trimming
  • Genome alignment
  • BAM file manipulation
  • Gene quantification
  • Bioinformatics workflow management

Applications

This preprocessing workflow provides the required inputs for downstream analyses such as:

  • Differential Gene Expression (DESeq2)
  • edgeR
  • limma-voom
  • Functional Enrichment Analysis
  • GO Analysis
  • KEGG Pathway Analysis

Future Improvements

Future versions of this project will include:

  • Multiple biological replicates
  • Differential expression analysis using DESeq2
  • Volcano plots
  • PCA visualization
  • Heatmaps
  • Gene Ontology enrichment
  • KEGG pathway analysis
  • Workflow automation using Bash

References

Kim D, Langmead B, Salzberg SL.

HISAT2: graph-based alignment of next-generation sequencing reads to a population of genomes.

Nature Biotechnology.


Liao Y, Smyth GK, Shi W.

featureCounts: an efficient general-purpose program for assigning sequence reads to genomic features.

Bioinformatics.


Andrews S.

FastQC: A Quality Control Tool for High Throughput Sequence Data.


Chen S, Zhou Y, Chen Y, Gu J.

fastp: an ultra-fast all-in-one FASTQ preprocessor.

Bioinformatics.


Author

Mehwish

Bioinformatics | RNA-seq Analysis | Linux | R | Python | NGS

GitHub: https://github.com/Mehwish55

About

A reproducible Linux-based RNA-seq preprocessing workflow including quality control, trimming, alignment, BAM processing, and gene-level quantification.

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