An in vitro method for modifying a genome within a mammalian cell that is heterozygous for a first allele, comprising: introducing into the cell: (a) a Cas protein or a nucleic acid encoding the Cas protein; (b) a first guide RNA or a DNA encoding the first guide RNA, wherein the first guide RNA hybridizes to a first non-allele-specific CRISPR RNA recognition sequence, wherein the first allele is on a first homologous chromosome and the CRISPR RNA recognition sequence is centromeric to a locus on a second homologous chromosome corresponding to the first allele; and (c) a second guide RNA or a DNA encoding the second guide RNA, wherein the second guide RNA hybridizes to a second non-allele-specific CRISPR RNA recognition sequence centromeric to the locus on the second homologous chromosome corresponding to the first allele, wherein the first allele is at least 100 kb from the first CRISPR RNA recognition sequence, wherein the Cas protein and the first guide RNA do not naturally occur together, wherein the Cas protein is a Cas9 protein and has nuclease activity on both strands of double-stranded DNA, and wherein the Cas protein cleaves the first CRISPR RNA recognition sequence to generate a double-strand break and the cell is modified to become homozygous for the first allele, optionally wherein the Cas protein cleaves the first CRISPR RNA recognition sequence and the second CRISPR RNA recognition sequence; and identifying a modified cell that is homozygous for the first allele. introducing into the cell: (a) a Cas protein or a nucleic acid encoding the Cas protein; (b) a first guide RNA or a DNA encoding the first guide RNA, wherein the first guide RNA hybridizes to a first non-allele-specific CRISPR RNA recognition sequence, wherein the first allele is on a first homologous chromosome and the CRISPR RNA recognition sequence is centromeric to a locus on a second homologous chromosome corresponding to the first allele; and (c) a second guide RNA or a DNA encoding the second guide RNA, wherein the second guide RNA hybridizes to a second non-allele-specific CRISPR RNA recognition sequence centromeric to the locus on the second homologous chromosome corresponding to the first allele, wherein the first allele is at least 100 kb from the first CRISPR RNA recognition sequence, wherein the Cas protein and the first guide RNA do not naturally occur together, wherein the Cas protein is a Cas9 protein and has nuclease activity on both strands of double-stranded DNA, and wherein the Cas protein cleaves the first CRISPR RNA recognition sequence to generate a double-strand break and the cell is modified to become homozygous for the first allele, optionally wherein the Cas protein cleaves the first CRISPR RNA recognition sequence and the second CRISPR RNA recognition sequence; and (a) a Cas protein or a nucleic acid encoding the Cas protein; (b) a first guide RNA or a DNA encoding the first guide RNA, wherein the first guide RNA hybridizes to a first non-allele-specific CRISPR RNA recognition sequence, wherein the first allele is on a first homologous chromosome and the CRISPR RNA recognition sequence is centromeric to a locus on a second homologous chromosome corresponding to the first allele; and (c) a second guide RNA or a DNA encoding the second guide RNA, wherein the second guide RNA hybridizes to a second non-allele-specific CRISPR RNA recognition sequence centromeric to the locus on the second homologous chromosome corresponding to the first allele, wherein the first allele is at least 100 kb from the first CRISPR RNA recognition sequence, wherein the Cas protein and the first guide RNA do not naturally occur together, wherein the Cas protein is a Cas9 protein and has nuclease activity on both strands of double-stranded DNA, and wherein the Cas protein cleaves the first CRISPR RNA recognition sequence to generate a double-strand break and the cell is modified to become homozygous for the first allele, optionally wherein the Cas protein cleaves the first CRISPR RNA recognition sequence and the second CRISPR RNA recognition sequence; and wherein the first allele is at least 100 kb from the first CRISPR RNA recognition sequence, wherein the Cas protein and the first guide RNA do not naturally occur together, wherein the Cas protein is a Cas9 protein and has nuclease activity on both strands of double-stranded DNA, and wherein the Cas protein cleaves the first CRISPR RNA recognition sequence to generate a double-strand break and the cell is modified to become homozygous for the first allele, optionally wherein the Cas protein cleaves the first CRISPR RNA recognition sequence and the second CRISPR RNA recognition sequence; and identifying a modified cell that is homozygous for the first allele.