Graph visualizations of MHC alleles

01 Nov 2016 | by Leo Rozenberg

The MHC gene family is well known for its polymorphism. The IPD-IMGT/HLA database provides the official reference sequences for the alleles found in this region. In addition, the Anthony Nolan HLA informatics group provides a reference alignment of these alleles.

Here is a pared clip (we insert ellipses to skip lines) of the output for the genetic DNA of HLA-A:

This format textually encodes differences between the reference sequence (the first one, A*01:01:01:01) and the other, alternate, allele sequences, along the file columns. Using special characters, the reader can tell if the alternate nucleotide is unknown (‘*’), the same (‘-‘), different (‘A’, ‘C’ …etc), or a gap (‘.’) to the known reference nucleotide in the same column.

While this format has its place, it isn’t useful for quickly visualizing the diversity of this region. We’ve created a small utility to marginally improve visualizing these alignments.

mhc2gpdf

As a graph

Our first intuition for this task was to compress the redundant sequence information. Grouping shared sequence segments as nodes led to us thinking about the entire alignment as a graph, and from this starting premise some properties followed naturally:

  • Alleles are represented by edges, such that one can trace the sequence of the allele by following edges.
  • Alignment information is preserved by adding a numerical label of alignment position. Different nucleotides at the same position are represented by different nodes: “336A” vs “336G”.
  • Gaps are encoded by the edges that point to nodes with a position farther than the position at the “end” of a node (the start label plus the length of the node sequence). In the example above, the “337GATGGAGCCG” node ends its position at 347 since len(GATGGAGCCG) = 10. Therefore there is a 20 nucleotide gap, in all of the alleles except “A*68:18N”, as indicated by the edge to “367CGGGC”.

Underneath the hood, mhc2gpdf first parses the alignment file; then constructs the desired graph representation by creating the desired nodes and edges; finally, it writes a dot file and calls Graphviz to render the dot file to PDF.

Samples

With these pdfs we can quickly determine allelic differences:

Carea

Appreciate the dense polymorphism of these genes:

Barea

And see long gaps in the Class II DRB nucleic sequences:

DRBgap

We’ve used our tool on the latest IMGT release (2016-10-19) and provide the dot and rendered pdfs: happy browsing!

Reading the graph

We’ve made some stylistic choices to make the graph easier to understand:

  • We run-length encode the leaf nodes of the tree that represents the allele edges: instead of “A*01:01:02,A*01:01:04,A*01:01:05…A*01:01:37”, we’ll write “A*01:01:02,04-37”.
  • If an edge represents more than half of the allele set, we’ll describe its complement and prefix the string with a “C. of”, short for “Complement of”.
  • We add “Start” nodes, prefixed with an “S” to indicate where the alignment has sequence data for each allele. These are similarly encoded as the edges.
  • We add “End” nodes for the same reason. These just have the final position.
  • We add “Boundary” nodes, which are represented by “|” in the alignment file for exome boundaries.

Feedback

We hope that the genetics community finds this tool useful and we look forward to your feedback on GitHub.