Methods for genome assembly and haplotype phasing

1. A method of genome assembly comprising:

obtaining a plurality of contigs;

complexing naked DNA with isolated nuclear proteins to form reconstituted chromatin;

generating a plurality of read pairs from data produced by probing the physical layout of the reconstituted chromatin;

mapping the plurality of read pairs to the plurality of contigs thereby producing read-mapping data; and

arranging the contigs using the read-mapping data to assemble the contigs into a genome assembly, such that contigs having common read pairs are positioned to determine a path through the contigs that represents their order to the genome.

2. The method of claim 1 , wherein the plurality of contigs is generated by using a shotgun sequencing method, comprising:

fragmenting a subject's DNA into random fragments of indeterminate size;

sequencing the fragments using high throughput sequence methods to generate a plurality of sequencing reads; and

assembling the sequencing reads so as to form the plurality of contigs.

3. The method of claim 1 , wherein generating a plurality of read pairs from data produced by probing the physical layout of reconstituted chromatin comprises using crosslinking.

4. The method of claim 1 , wherein generating a plurality of read pairs from data produced by probing the physical layout of reconstituted chromatin comprises:

crosslinking reconstituted chromatin with a fixative agent to form DNA-protein cross links;

cutting the cross-linked DNA-Protein with one or more restriction enzymes so as to generate a plurality of DNA-Protein complexes comprising sticky ends;

filling in the sticky ends with nucleotides containing one or more markers to create blunt ends that are then ligated together;

fragmenting the plurality of DNA-protein complexes into fragments;

pulling down junction-containing fragments by using the one or more markers; and

sequencing the junction containing fragments using high throughput sequencing methods to generate the plurality of read pairs.

5. The method of claim 1 , wherein the isolated nuclear proteins comprise isolated histones.

6. The method of claim 1 , wherein for the plurality of read pairs, read pairs are weighted by taking a function of a read's distance to the edge of a mapped contig so as to incorporate a higher probability of shorter contacts than longer contacts.

7. The method of claim 1 , wherein the method provides for the genome assembly of a human subject, and wherein the plurality of read pairs is generated by using the human subject's reconstituted chromatin made from the subject's naked DNA.

8. The method of claim 1 , wherein the method further comprises:

identifying one or more sites of heterozygosity in the plurality of read pairs; and

identifying read pairs that comprise a pair of heterozygous sites, wherein phasing data for allelic variants can be determined from the identification of the pair of heterozygous sites.

9. The method of claim 1 , wherein said arranging the contigs using the read pair data comprises:

constructing an adjacency matrix of contigs using the readmapping data; and

analyzing the adjacency matrix to determine a path through the contigs that represents their order in the genome.

10. The method of claim 9 , comprising analyzing the adjacency matrix to determine a path through the contigs that represents their order and orientation to the genome.

11. The method of claim 9 , wherein a read pair is weighted as a function of the distance from the mapped position of its first read on a first contig to the edge of that first contig and the distance from the mapped position of its second read on a second contig to the edge of that second contig.

12. The method of claim 7 , wherein the plurality of contigs is generated from the human subject's DNA.

13. The method of claim 1 , wherein the genome assembly represents the contigs' order and orientation.

14. The method of claim 1 , wherein a read pair is weighted as a function of the distance from the mapped position of its first read on a first contig to the edge of that first contig and the distance from the mapped position of its second read on a second contig to the edge of that second contig.

15. The method of claim 1 , wherein read pairs that map to different contigs provide data about which contigs are adjacent in a correct genome assembly.