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A new density-modification procedure extending the application of the recent |ρ|-based phasing algorithm to larger crystal structures.

ABSTRACT: The incorporation of the new peakness-enhancing fast Fourier transform compatible ipp procedure (ipp = inner-pixel preservation) into the recently published S_M algorithm based on |ρ| [Rius (2020). Acta Cryst A76, 489-493] improves its phasing efficiency for larger crystal structures with atomic resolution data. Its effectiveness is clearly demonstrated via a collection of test crystal structures (taken from the Protein Data Bank) either starting from random phase values or by using the randomly shifted modulus function (a Patterson-type synthesis) as initial ρ estimate. It has been found that in the presence of medium scatterers (e.g. S or Cl atoms) crystal structures with 1500 × c atoms in the unit cell (c = number of centerings) can be routinely solved. In the presence of strong scatterers like Fe, Cu or Zn atoms this number increases to around 5000 × c atoms. The implementation of this strengthened S_M algorithm is simple, since it only includes a few easy-to-adjust parameters.

SUBMITTER: Rius J

PROVIDER: S-EPMC8248888 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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A new density-modification procedure extending the application of the recent |ρ|-based phasing algorithm to larger crystal structures.

Rius Jordi J Torrelles Xavier X

Acta crystallographica. Section A, Foundations and advances 20210621 Pt 4

The incorporation of the new peakness-enhancing fast Fourier transform compatible ipp procedure (ipp = inner-pixel preservation) into the recently published S<sub>M</sub> algorithm based on |ρ| [Rius (2020). Acta Cryst A76, 489-493] improves its phasing efficiency for larger crystal structures with atomic resolution data. Its effectiveness is clearly demonstrated via a collection of test crystal structures (taken from the Protein Data Bank) either starting from random phase values or by using th ...[more]

PMID: 34196295

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Project description:BackgroundWe describe the latest improvements to the long-range phasing (LRP) and haplotype library imputation (HLI) algorithms for successful phasing of both datasets with one million individuals and datasets genotyped using different sets of single nucleotide polymorphisms (SNPs). Previous publicly available implementations of the LRP algorithm implemented in AlphaPhase could not phase large datasets due to the computational cost of defining surrogate parents by exhaustive all-against-all searches. Furthermore, the AlphaPhase implementations of LRP and HLI were not designed to deal with large amounts of missing data that are inherent when using multiple SNP arrays.MethodsWe developed methods that avoid the need for all-against-all searches by performing LRP on subsets of individuals and then concatenating the results. We also extended LRP and HLI algorithms to enable the use of different sets of markers, including missing values, when determining surrogate parents and identifying haplotypes. We implemented and tested these extensions in an updated version of AlphaPhase, and compared its performance to the software package Eagle2.ResultsA simulated dataset with one million individuals genotyped with the same 6711 SNPs for a single chromosome took less than a day to phase, compared to more than seven days for Eagle2. The percentage of correctly phased alleles at heterozygous loci was 90.2 and 99.9% for AlphaPhase and Eagle2, respectively. A larger dataset with one million individuals genotyped with 49,579 SNPs for a single chromosome took AlphaPhase 23 days to phase, with 89.9% of alleles at heterozygous loci phased correctly. The phasing accuracy was generally lower for datasets with different sets of markers than with one set of markers. For a simulated dataset with three sets of markers, 1.5% of alleles at heterozygous positions were phased incorrectly, compared to 0.4% with one set of markers.ConclusionsThe improved LRP and HLI algorithms enable AlphaPhase to quickly and accurately phase very large and heterogeneous datasets. AlphaPhase is an order of magnitude faster than the other tested packages, although Eagle2 showed a higher level of phasing accuracy. The speed gain will make phasing achievable for very large genomic datasets in livestock, enabling more powerful breeding and genetics research and application.

Project description:BackgroundFailing the four-gamete test for two polymorphic DNA markers is an indication that two or three rather than four haplotypes segregate in the population. The objective of this paper is to show that when just three haplotypes are segregating, all three haplotypes can be fully and unambiguously phase-resolved.Theory and methodsThe Corners' Algorithm tests the four corners in a 3 × 3 table of two-locus genotypes. If one of the four corners is filled with zeroes, then the missing haplotype is identified and the phases of all three haplotypes can be unambiguously resolved for all individuals. Three applications of this method are proposed when the four-gamete test fails: (1) direct estimation of linkage disequilibrium (LD), (2) haplotype-based genome-wide association studies (GWAS) of three haplotypes (single-marker GWAS tests for two out of three haplotypes only), and (3) haplotyping of chromosomal regions that are comprised of pairs of single nucleotide polymorphisms (SNPs) that consist of just three haplotypes. An example based on 435 sows with performance records for total number of piglets born is used to illustrate the methods.ResultsOf 20,339 SNPs, approximately 50% of the pairs of flanking SNPs failed the four-gamete test. For those, the expectation maximization (EM) algorithm gave the same results. The average of the absolute value of the difference in r2 between flanking SNPs across the genome between the two methods was 0.00082. Single-marker GWAS (using two of three haplotypes) detected significant associations for total number of piglets born on chromosomes 1, 2, 6, 9, 10, 12, 13, 14, 15, and 18. Haplotype-based GWAS using the third haplotype resolved with the Corners' Algorithm detected additional significant associations for total number of piglets born on chromosomes 2, 5, 10, 13, 14, 15, and 18. Estimated substitution effects ranged from 0.40 to 1.35 piglets. Haplotyping of chromosomal regions that failed the four-gamete test for any pair of SNPs covered 961 Mb out of the 2249 Mb by the SNP array.ConclusionsThe Corner's Algorithm allows to fully phase haplotypes when the four-gamete test fails. Longer haplotypes in chromosomal regions in which the four-gamete test fails for any pair of SNPs can be used as a multi-allelic marker with increased polymorphism information content.

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A new density-modification procedure extending the application of the recent |ρ|-based phasing algorithm to larger crystal structures.

Publications

A new density-modification procedure extending the application of the recent |ρ|-based phasing algorithm to larger crystal structures.

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