Archaic Introgression Analysis Service

Overview

Archaic introgression analysis is a specialized genomic research approach. It focuses on detecting and interpreting genetic material. This genetic material is inherited from archaic hominins, like Neanderthals and Denisovans, into modern human genomes. These introgressed segments still exist in present-day populations. They have contributed to adaptive traits, disease susceptibility, and human phenotypic diversity. Our service uses advanced computational and genomic tools. It maps archaic introgression, assesses its functional and evolutionary impacts, and offers insights into its role in shaping modern human biology.

Our Archaic Introgression Analysis Service Offers:

• High-Precision Introgression Detection:
  Utilize deep whole-genome sequencing data and machine learning-based methods (e.g., S* and Sprime). These methods help identify archaic-derived haplotypes with high confidence. This is possible even in regions of low complexity or recent gene flow. We use reference panels of archaic and modern human genomes. They help us distinguish introgressed segments from ancestral variation.
• Comparative Genomics and Ancestry Mapping:
  Employ comparative genomics. It is across diverse modern human populations and archaic hominins. This helps us trace the geographic and demographic distribution of introgressed regions. We annotate lineage-specific adaptations. For example, high-altitude adaptation in Tibetans is linked to Denisovan EPAS1. We also identify regions subject to positive selection.
• Functional Impact and Disease Association Analysis:
  Predict the biological effects of introgressed variants. We use in silico tools (e.g., RegulomeDB, DeepSEA) for this. We integrate functional genomic datasets (e.g., eQTLs, chromatin accessibility). This helps us assess their role in gene regulation, protein function, or disease risk. We highlight variants linked to immune responses, metabolic traits, and neurological disorders.
• Evolutionary Dynamics and Population History Reconstruction:
  Analyze patterns of introgression frequency, linkage disequilibrium, and haplotype structure. This helps us infer the timing and strength of selection acting on archaic alleles. We use coalescent simulations and demographic modeling. They help us reconstruct population history events, such as admixture pulses and purifying selection against maladaptive variants.
• Customized Visualization and Reporting:
  Provide interactive, publication-ready visualizations of introgressed regions, including Manhattan plots, haplotype networks, and selection scans. Our reports summarize key findings, evolutionary interpretations, and potential implications for health and ancestry, tailored to research or clinical applications.

Archaic Introgression Analysis is a pioneering genomic methodology dedicated to detecting and interpreting the legacy of interbreeding events between anatomically modern humans and archaic hominins, such as Neanderthals and Denisovans. These ancient gene flow episodes introduced archaic-derived alleles into the modern human genome, which have since been shaped by natural selection, genetic drift, and demographic processes. By systematically characterizing archaic introgressed segments—including their frequency, distribution, and functional impacts—researchers can elucidate how these ancestral genetic variants influenced adaptive traits (e.g., immune responses, high-altitude adaptation, skin pigmentation), susceptibility to diseases, and the evolutionary trajectory of human populations. This approach not only sheds light on the mosaic nature of the human genome but also provides critical insights into the dynamic interplay between hybridization, adaptation, and survival across deep evolutionary timescales.

How to Measure

1. Sample Collection and Preparation

Sample Types:

• Human: Blood, saliva, buccal swabs, or ancient DNA (aDNA) from fossils/bones.
• Archaic Hominins: Neanderthal/Denisovan remains (e.g., teeth, long bones) for high-quality aDNA extraction.
• Environmental/Microbial: Soil or sediment samples from archaic habitat sites (for metagenomic reconstruction of extinct microbiomes).

Genotyping/Sequencing Technologies for Archaic Introgression Detection:

Table 1: Key Methods and Their Characteristics

Data Quality Control (QC):

• Sample-Level: Exclude samples with low DNA integrity (e.g., high fragmentation in aDNA), contamination (>2% non-human DNA), or insufficient coverage (<1× for aDNA).
• Data-Level: Filter out low-confidence calls (e.g., introgressed tracts <10 kb or <5 supporting reads; SNPs with missingness >5%).

2. Statistical Analysis Workflow for Archaic Introgression

Introgression Detection and Segmentation:

• Tools:
  • S-STARR (for archaic haplotype phasing).
  • ArchaicSeeker 2.0 (machine learning-based detection).
  • Sprime (identifies adaptive introgression under selection).
• Approach: Use HMMs or likelihood-ratio tests to distinguish archaic vs. modern human ancestry. Define introgressed tracts by breakpoint accuracy (>95% confidence).

Population-Level Analysis:

• Frequency Estimation: Calculate archaic allele frequencies across populations (e.g., higher in East Asians vs. Africans for Denisovan ancestry).
• Selection Tests:
  • iHS (integrated haplotype score) for ongoing selection.
  • PBS (population branch statistic) to identify rapid frequency shifts.
• Admixture Graphs: Model gene flow between archaic and modern populations (e.g., using TreeMix or ADMIXTOOLS).

Functional Annotation:

• Gene Overlap: Prioritize introgressed variants in coding regions, promoters, or enhancers (e.g., HYAL2 for Neanderthal-derived immune adaptation).
• Pathway Enrichment: Test for overrepresentation in disease-related pathways (e.g., TLR1 variants linked to autoimmune disorders).
• Regulatory Impact: Predict effects on transcription factor binding (e.g., using RegulomeDB or DeepSEA).

3. Visualization and Reporting of Archaic Introgression

Visualization Tools:

• Circos Plots: Display introgressed tracts across chromosomes (e.g., Neanderthal segments in non-African genomes).
• Manhattan Plots: Highlight genomic regions under selection (e.g., EPAS1 in Tibetans for high-altitude adaptation).
• Haplotype Networks: Compare archaic and modern haplotypes (e.g., BNC2 for skin pigmentation).
• IGV: Manually inspect read alignments to confirm introgression breakpoints.

Significance Thresholds:

• Tract Length: ≥10 kb (for confident archaic ancestry assignment).
• Statistical Significance:
  • p < 1×10⁻⁸ (Bonferroni-corrected for genome-wide scans).
  • q < 0.05 (FDR-corrected for multiple testing in pathway analysis).

Reporting Guidelines:

• Include metadata (e.g., ancestry, sequencing depth, contamination estimates).
• Report both raw and phased introgressed tracts with confidence scores.
• Discuss functional implications (e.g., "Denisovan-derived TBX15 variant associated with fat distribution in Oceanians").

Figure 1: Archaic introgression Analysis

What Can We do

Archaic Haplotype Screening: We use reference-quality archaic genomes, like Neanderthal and Denisovan genomes. We use tools such as Sprime and ArchaicSeeker 2.0 to identify introgressed segments in modern human populations. We focus on regions with high divergence from African-ancestry genomes. This helps us prioritize adaptive variants.

Our Advantages

Applications

1. Human Evolutionary Genetics

Archaic introgression analysis plays a pivotal role in human evolutionary genetics by identifying genomic regions inherited from Neanderthals, Denisovans, or other archaic hominins. These regions provide insights into adaptive traits such as immune responses, lipid metabolism, and high-altitude adaptation, revealing how ancient gene flow contributed to the survival and diversification of modern human populations.

2. Disease Susceptibility Studies

By mapping archaic introgressed alleles in contemporary human genomes, researchers can investigate their associations with disease risk. For example, certain Neanderthal-derived variants have been linked to autoimmune disorders, neurological conditions, and viral resistance, offering clues about the evolutionary trade-offs between adaptation and health vulnerabilities.

3. Population Genomics and Demographic History

Archaic introgression analysis helps reconstruct ancient population interactions and migration patterns. By quantifying the extent and distribution of archaic ancestry across global populations, scientists can infer the timing, geographic scope, and selective pressures shaping modern human genetic diversity, enhancing our understanding of human prehistory.

4. Functional Genomics and Gene Regulation

Studying archaic introgressed regions enables the exploration of gene regulatory evolution. Comparative analyses of archaic and modern human regulatory elements reveal how these variants influence gene expression patterns, potentially explaining phenotypic differences between archaic and modern humans and their role in adaptive evolution.

Demo

Figure 2: Fine-scale genetic structure of the modern Japanese and its three ancestry origins. (Liu, 2024)

Case Study

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