Abstract: Disclosed is a method for introducing a plurality of programmed nucleotide modifications into a single locus of a desired genomic DNA sequence in a single experiment. The method entails synthesizing a homology-directed repair (HDR) library comprising a plurality of oligonucleotides, wherein each oligonucleotide comprises a programmed nucleotide modification in the locus of the desired genome, and co-transfecting a population of cells with (i) an expression system capable of expressing Cas9 and a single guide RNA (sgRNA) and (ii) introducing a plurality of programmed nucleotide modifications to the locus of the desired genomic DNA sequence in one or more cells of the population. Also disclosed are methods for analyzing the functional consequence of a genomic mutation and for genomic screening.

Abstract: Methods and apparatus are provided for designing molecular inversion probes (MIPs). A computing device can determine representations of sequence features of a reference genome. The computing device can assess target arms that meet design criteria for a MIP in matching the representations of sequence features. For each pair of target arms that meet the design criteria, the computing device can: determine MIP performance data features for the pair, and determine a score for the pair using a MIP performance model operating on the MIP performance data features for the pair. The computing device can determine a subset of the target arms that collectively tile all of the sequence features, where the subset is determined based on the target arm scores. The computing device can determine designed MIPs based on the subset of target arms. The computing device can output information about each designed MIP.